Gene Summary

Gene:ARHGEF5; Rho guanine nucleotide exchange factor 5
Aliases: P60, TIM, GEF5, TIM1
Summary:Rho GTPases play a fundamental role in numerous cellular processes initiated by extracellular stimuli that work through G protein coupled receptors. The encoded protein may form a complex with G proteins and stimulate Rho-dependent signals. This protein may be involved in the control of cytoskeletal organization. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:rho guanine nucleotide exchange factor 5
Source:NCBIAccessed: 31 August, 2019


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

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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

  • Cyclin D1
  • Base Sequence
  • Trans-Activators
  • src-Family Kinases
  • COS Cells
  • Actins
  • NIH 3T3 Cells
  • Cell Survival
  • Promoter Regions
  • Polymerase Chain Reaction
  • Basic Helix-Loop-Helix Transcription Factors
  • China
  • MMP2
  • Smoking
  • Up-Regulation
  • Endometrial Cancer
  • Air Pollution
  • Alternative Splicing
  • Amino Acid Sequence
  • Molecular Sequence Data
  • Genome, Human
  • Immunohistochemistry
  • Guanine Nucleotide Exchange Factors
  • ARNTL Transcription Factors
  • Immunoblotting
  • Lung Cancer
  • Chromosome 7
  • Adenocarcinoma
  • Carcinogenesis
  • Circadian Rhythm
  • Whole Genome Sequencing
  • Breast Cancer
  • Non-Small Cell Lung Cancer
  • Rho Guanine Nucleotide Exchange Factors
  • Carcinoma
  • Nuclear Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

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: ARHGEF5 (cancer-related)

Ishida E, Lee J, Campbell JS, et al.
Intratumoral delivery of an HPV vaccine elicits a broad anti-tumor immune response that translates into a potent anti-tumor effect in a preclinical murine HPV model.
Cancer Immunol Immunother. 2019; 68(8):1273-1286 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1

Holland BC, Sood A, Delfino K, et al.
Age and sex have no impact on expression levels of markers of immune cell infiltration and immune checkpoint pathways in patients with muscle-invasive urothelial carcinoma of the bladder treated with radical cystectomy.
Cancer Immunol Immunother. 2019; 68(6):991-997 [PubMed] Related Publications
OBJECTIVES: Advanced age and female sex have been associated with worse outcomes in patients undergoing radical cystectomy for muscle-invasive bladder cancer. A reduced immune response has been implicated as a mechanism. The objective of our study was to analyze the expression patterns of various cellular proteins active in bladder cancer immune pathways, and assess the correlation between age, sex, and the expression of these immune markers.
METHODS: We obtained surgical tissue samples from equally distributed male/female patients with/without lymph node metastasis who had undergone radical cystectomy for urothelial carcinoma (UC) of the bladder (n = 50). Immunohistochemistry (IHC) for CD3 (cluster of differentiation), CD4, CD8, CD56, LAG-3 (lymphocyte-activation gene), TIM-3 (T-cell immunoglobulin and mucin-domain), PD-1 (programmed death) and PD-L1 molecules was performed and scored by a single pathologist (high versus low). Spearman's correlation and Chi square tests investigated the association between age, sex, and IHC results.
RESULTS: Mean age at surgery was 67 years (range 50-78 years); all patients were Caucasians. The following percent of patients scored high for a stain: 18% CD3, 10% CD4, 0% CD8, 0% CD56, 20% LAG-3, 4% TIM-3, 0% PD-1 and 0% PD-L1. There was no association between patients' age, sex, and the expression of any of the immune markers (p > 0.05 for all).
CONCLUSIONS: The association between advanced age, female sex, and worse outcomes in bladder cancer may be independent of the immune pathways active in the disease that we examined in this study.

Mollica V, Di Nunno V, Gatto L, et al.
Novel Therapeutic Approaches and Targets Currently Under Evaluation for Renal Cell Carcinoma: Waiting for the Revolution.
Clin Drug Investig. 2019; 39(6):503-519 [PubMed] Related Publications
Management of metastatic renal cell carcinoma has drastically changed in the last few years, witnessing the advent of more and more target therapies and, recently, of immune-checkpoint inhibitors. On the other hand, the adjuvant setting still lacks a clear beneficial treatment. Medical treatment still remains a compelling challenge. A large number of clinical trials is ongoing with the aim to identify new therapeutic approaches to expand the options in our repertoire. Several strategies are under investigation in renal cell carcinoma (RCC). These include new targeted agents and combinations of target therapy and immunotherapy. Programmed death receptor-1 (PD-1), programmed death receptor ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA4) are just part of the intricate network that regulates our immune response to cancer cells. Co-stimulators, such as glucocorticoid-induced TNFR-related protein (GITR) and tumor necrosis factor receptor superfamily, member 4 (OX40), and co-repressors, example.g. T cell immunoglobulin and mucin domain 3 (TIM-3) and lymphocyte-activation gene 3 (LAG-3), also take part. As knowledge of the functioning of the immune system grows, so do these pathways to target with new drugs. This review is an overview of the current state of the clinical research, providing a report of ongoing Phase I, II and III clinical trials for localized and metastatic RCC, including novel target therapies, novel immunotherapy agents and new combinations strategies.

Noviello M, Manfredi F, Ruggiero E, et al.
Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT.
Nat Commun. 2019; 10(1):1065 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (T

Long J, Wang A, Bai Y, et al.
Development and validation of a TP53-associated immune prognostic model for hepatocellular carcinoma.
EBioMedicine. 2019; 42:363-374 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: TP53 mutation is the most common mutation in hepatocellular carcinoma (HCC), and it affects the progression and prognosis of HCC. We investigated how TP53 mutation regulates the HCC immunophenotype and thus affects the prognosis of HCC.
METHODS: We investigated TP53 mutation status and RNA expression in different populations and platforms and developed an immune prognostic model (IPM) based on immune-related genes that were differentially expressed between TP53
FINDINGS: TP53 mutation resulted in the downregulation of the immune response in HCC. Thirty-seven of the 312 immune response-related genes were differentially expressed based on TP53 mutation status. An IPM was established and validated based on 865 patients with HCC to differentiate patients with a low or high risk of poor survival. A nomogram was also established for clinical application. Functional enrichment analysis showed that the humoral immune response and immune system diseases pathway represented the major function and pathway, respectively, related to the IPM genes. Moreover, we found that the patients in the high-risk group had higher fractions of T cells follicular helper, T cells regulatory (Tregs) and macrophages M0 and presented higher expression of CTLA-4, PD-1 and TIM-3 than the low-risk group.
INTERPRETATION: TP53 mutation is strongly related to the immune microenvironment in HCC. Our IPM, which is sensitive to TP53 mutation status, may have important implications for identifying subgroups of HCC patients with low or high risk of unfavourable survival. FUND: This work was supported by the International Science and Technology Cooperation Projects (2016YFE0107100), the Capital Special Research Project for Health Development (2014-2-4012), the Beijing Natural Science Foundation (L172055 and 7192158), the National Ten Thousand Talent Program, the Fundamental Research Funds for the Central Universities (3332018032), and the CAMS Innovation Fund for Medical Science (CIFMS) (2017-I2M-4-003 and 2018-I2M-3-001).

Duan M, Goswami S, Shi JY, et al.
Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma.
Clin Cancer Res. 2019; 25(11):3304-3316 [PubMed] Related Publications
PURPOSE: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).
RESULTS: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7
CONCLUSIONS: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.

Wu K, Zhao H, Xiu Y, et al.
IL-21-mediated expansion of Vγ9Vδ2 T cells is limited by the Tim-3 pathway.
Int Immunopharmacol. 2019; 69:136-142 [PubMed] Related Publications
Vγ9Vδ2 T cells are the main γδ T subset in the peripheral blood and lymphoid organs. Previous studies have shown that Vγ9Vδ2 T cells could expand in the presence of phosphoantigens and IL-2 and exert antitumor functions. However, their potency was limited because sustained proliferation could not be achieved, possibly due to exhaustion caused by prolonged antigenic stimulation. In this study, we examined the proliferative response of Vγ9Vδ2 T cells to IL-21, a cytokine previously shown to promote NK cell and CD8 T cell cytotoxicity. We found that IL-21 could significantly improve the proliferation of phosphoantigen-stimulated Vγ9Vδ2 T cells in a dose-dependent manner. However, in acute myeloid leukemia (AML) patients, the efficacy of IL-21 was significantly reduced. Vγ9Vδ2 T cells from AML patients exhibited lower expression of IL-21R, and required higher levels of IL-21 for expansion. IL-21-treated Vγ9Vδ2 T cells from AML patients presented lower increase in STAT1 phosphorylation than Vγ9Vδ2 T cells from healthy volunteers. Interestingly, AML Vγ9Vδ2 T cells presented significantly higher Tim-3 expression than healthy Vγ9Vδ2 T cells. IL-21 treatment further induced Tim-3 upregulation. Blocking Tim-3 increased the proliferation and the STAT phosphorylation in Vγ9Vδ2 T cells in response to IL-21. Together, these results demonstrated that IL-21 could significantly expand the Vγ9Vδ2 T cells, but its efficacy was limited since it also increased the expression of checkpoint molecule Tim-3.

Agdashian D, ElGindi M, Xie C, et al.
The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma.
Cancer Immunol Immunother. 2019; 68(4):599-608 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Checkpoint inhibitors have recently been approved for the treatment of patients with hepatocellular carcinoma (HCC). However, biomarkers, which will help identify patients responding to therapy, are missing. We recently tested the combination of anti-CTLA4 treatment (tremelimumab) with loco-regional therapy in patients with HCC and reported a partial response rate of 26%.
METHODS: Here, we report updated survival analyses and results from our immune monitoring studies on peripheral blood mononuclear cells (PBMCs) and tumors from these patients.
RESULTS: Tremelimumab therapy increased CD4
CONCLUSION: In summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4.

Zhang X, Yin X, Zhang H, et al.
Differential expression of TIM-3 between primary and metastatic sites in renal cell carcinoma.
BMC Cancer. 2019; 19(1):49 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
BACKGROUND: Due to the significant heterogeneity of renal cell carcinoma (RCC), immune checkpoints may express differently between primary and metastatic tumor. We aimed to evaluate the differential expression of TIM-3 between the primary and metastatic sites of RCC.
METHODS: Cases of RCC with metastases resected or biopsied at West China Hospital between January 2009 and November 2016 were included. Clinicopathological parameters were retrospectively extracted. SPPS 22.0, GraphPad Prism 6 and R statistical software were applied for data analysis.
RESULTS: A total of 163 cases were included. Immunohistochemical results showed that the overall detection rate of TIM-3 was 56.4% (92/163). The detection rate of TIM-3 in the primary (53.0%, 44/83) was numerically higher than that of the metastasis (42.6%,79/174). Although the concordance rate of TIM-3 between the primary and metastasis was as high as 66.3% (55/83) in the paired cohort, a significant statistically difference of TIM-3 expression between the primary and metastasis was observed (χ2 = 4.664, p = 0.002), with a poor consistency (Kappa = 0.331, p = 0.002). Subsequent survival analysis suggested that TIM-3 expression either in the primary or metastatic tumor was associated with longer progression-free survival (PFS) (HR: 0.67, 95% CI 0.45-0.99, P = 0.02) and overall survival (OS) (HR: 0.52, 95% CI 0.33-0.82, P < 0.001). The expressions of TIM-3 in the primary, metastatic tumors and patients treated with targeted agents all played as favorable factors for PFS and OS. Further multivariate analysis showed that, in the whole cohort, TIM-3 expression in metastatic tumor increased the predicted accuracy (PA) of the whole model of PFS from 74.7 to 75.6% (P = 0.02). For OS, the PA of whole model was increased from 78.1 to 81.1% by adding TIM-3 expression in the metastasis (P = 0.005). The same trends were also observed in paired patients and patients treated with targeted agents. In conclusion, the expression difference between the primary and metastatic tumor of TIM-3 was significant. Biopsy or resection of the metastases may provide a more accurate biological information for clinician's decision-making and the patient's prognosis. What's more, the role of TIM-3 in the RCC still remains controversy, further study are needed to verify the conclusion.

Yun SJ, Lee B, Komori K, et al.
Regulation of TIM-3 expression in a human T cell line by tumor-conditioned media and cyclic AMP-dependent signaling.
Mol Immunol. 2019; 105:224-232 [PubMed] Related Publications
T cell immunoglobulin and mucin domain-3 (TIM-3) expression increases in exhausted T cells, which inhibits T cell function. TIM-3 expression is supposedly up-regulated in tumor-bearing individuals via chronic antigenic stimulation of T cells. Considering the immunosuppressive nature of the tumor microenvironment, we investigated whether tumor-secreted molecules might enhance TIM-3 expression in Jurkat T cells. We observed that TIM-3 expression was increased by the activation of prostaglandin (PG) E

Liu L, Song Z, Zhao Y, et al.
HAVCR1 expression might be a novel prognostic factor for gastric cancer.
PLoS One. 2018; 13(11):e0206423 [PubMed] Article available free on PMC after 01/08/2020 Related Publications
Hepatitis A virus cellular receptor 1 (HAVCR1), which is also known as T-cell immunoglobulin and mucin domain 1 (TIM-1) is a TIM gene family member. In this study, we aimed to characterize the expression profile of HAVCR1 in GC, its prognostic value and the potential epigenetic mechanism leading to its dysregulation. Bioinformatic analysis was performed by using genomic, clinicopathological and survival data in the human protein atlas (HPA) and the Cancer Genome Atlas (TCGA). Results showed that HAVCR1 was significantly upregulated at the mRNA and protein level in GC tissues compared to the adjacent normal tissues. In addition, HAVCR1 upregulation was an independent indicator of shorter OS (HR: 1.698, 95%CI: 1.221-2.361, p = 0.002), after adjustment of older age, differentiation status, pathological stages and the presence of residual tumor and was also an independent indicator of shorter RFS (HR: 2.577, 95%CI: 1.583-4.197, p<0.001), after adjustment of gender and histological grade. The methylation level of two CpG sites (cg11188031 and cg07320595) was negatively correlated with HAVCR1 expression. However, only high methylation level of cg07320595 was associated with significantly longer OS (p = 0.018) and RFS (p = 0.021). Based on these findings, we infer that HAVCR1 upregulation might serve as a valuable prognostic marker in terms of OS and RFS in GC patients. Cg07320595 might be a critical CpG site influencing HAVCR1 expression.

McCaw TR, Li M, Starenki D, et al.
The expression of MHC class II molecules on murine breast tumors delays T-cell exhaustion, expands the T-cell repertoire, and slows tumor growth.
Cancer Immunol Immunother. 2019; 68(2):175-188 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
The expression of MHC class II molecules (MHCII) on tumor cells correlates with survival and responsiveness to immunotherapy. However, the mechanisms underlying these observations are poorly defined. Using a murine breast tumor line, we showed that MHCII-expressing tumors grew more slowly than controls and recruited more functional CD4

Goovaerts T, Steyaert S, Vandenbussche CA, et al.
A comprehensive overview of genomic imprinting in breast and its deregulation in cancer.
Nat Commun. 2018; 9(1):4120 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Genomic imprinting plays an important role in growth and development. Loss of imprinting (LOI) has been found in cancer, yet systematic studies are impeded by data-analytical challenges. We developed a methodology to detect monoallelically expressed loci without requiring genotyping data, and applied it on The Cancer Genome Atlas (TCGA, discovery) and Genotype-Tissue expression project (GTEx, validation) breast tissue RNA-seq data. Here, we report the identification of 30 putatively imprinted genes in breast. In breast cancer (TCGA), HM13 is featured by LOI and expression upregulation, which is linked to DNA demethylation. Other imprinted genes typically demonstrate lower expression in cancer, often associated with copy number variation and aberrant DNA methylation. Downregulation in cancer frequently leads to higher relative expression of the (imperfectly) silenced allele, yet this is not considered canonical LOI given the lack of (absolute) re-expression. In summary, our novel methodology highlights the massive deregulation of imprinting in breast cancer.

Polewko-Klim A, Lesiński W, Mnich K, et al.
Integration of multiple types of genetic markers for neuroblastoma may contribute to improved prediction of the overall survival.
Biol Direct. 2018; 13(1):17 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Modern experimental techniques deliver data sets containing profiles of tens of thousands of potential molecular and genetic markers that can be used to improve medical diagnostics. Previous studies performed with three different experimental methods for the same set of neuroblastoma patients create opportunity to examine whether augmenting gene expression profiles with information on copy number variation can lead to improved predictions of patients survival. We propose methodology based on comprehensive cross-validation protocol, that includes feature selection within cross-validation loop and classification using machine learning. We also test dependence of results on the feature selection process using four different feature selection methods.
RESULTS: The models utilising features selected based on information entropy are slightly, but significantly, better than those using features obtained with t-test. The synergy between data on genetic variation and gene expression is possible, but not confirmed. A slight, but statistically significant, increase of the predictive power of machine learning models has been observed for models built on combined data sets. It was found while using both out of bag estimate and in cross-validation performed on a single set of variables. However, the improvement was smaller and non-significant when models were built within full cross-validation procedure that included feature selection within cross-validation loop. Good correlation between performance of the models in the internal and external cross-validation was observed, confirming the robustness of the proposed protocol and results.
CONCLUSIONS: We have developed a protocol for building predictive machine learning models. The protocol can provide robust estimates of the model performance on unseen data. It is particularly well-suited for small data sets. We have applied this protocol to develop prognostic models for neuroblastoma, using data on copy number variation and gene expression. We have shown that combining these two sources of information may increase the quality of the models. Nevertheless, the increase is small and larger samples are required to reduce noise and bias arising due to overfitting.
REVIEWERS: This article was reviewed by Lan Hu, Tim Beissbarth and Dimitar Vassilev.

Oda K, Hamanishi J, Matsuo K, Hasegawa K
Genomics to immunotherapy of ovarian clear cell carcinoma: Unique opportunities for management.
Gynecol Oncol. 2018; 151(2):381-389 [PubMed] Related Publications
Ovarian clear cell carcinoma (OCCC) is distinctive from other histological types of epithelial ovarian cancer, with genetic/epigenetic alterations, a specific immune-related molecular profile, and epidemiologic associations with ethnicity and endometriosis. These findings allow for the exploration of unique and specific treatments for OCCC. Two major mutated genes in OCCC are PIK3CA and ARID1A, which are frequently coexistent with each other. Other genes' alterations also contribute to activation of the PI3K (e.g. PIK3R1 and PTEN) and dysregulation of the chromatin remodeling complex (e.g. ARID1B, and SMARKA4). Although the number of focal copy number variations is small in OCCC, amplification is recurrently detected at chromosome 20q13.2 (including ZNF217), 8q, and 17q. Both expression and methylation profiling highlight the significance of adjustments to oxidative stress and inflammation. In particular, up-regulation of HNF-1β resulting from hypomethylation contributes to the switch from anaerobic to aerobic glucose metabolism. Additionally, up-regulation of HNF-1β activates STAT3 and NF-κB signaling, and leads to immune suppression via production of IL-6 and IL-8. Immune suppression may also be induced by the increased expression of PD-1, Tim-3 and LAG3. Mismatch repair deficient (microsatellite instable) tumors as found in Lynch syndrome also induce immune suppression in some OCCC. In a recent phase II clinical trial in heavily-treated platinum-resistant ovarian cancer, two out of twenty cases with a complete response to the anti-PD-1 antibody, nivolumab, were OCCC subtypes. Thus, the immune-suppressive state resulting from both genetic alterations and the unique tumor microenvironment may be associated with sensitivity to immune checkpoint inhibitors in OCCC. In this review, we highlight recent update and progress in OCCC from both the genomic and immunologic points of view, addressing the future candidate therapeutic options.

Krstic J, Reinisch I, Schupp M, et al.
p53 Functions in Adipose Tissue Metabolism and Homeostasis.
Int J Mol Sci. 2018; 19(9) [PubMed] Article available free on PMC after 01/02/2020 Related Publications
As a tumor suppressor and the most frequently mutated gene in cancer, p53 is among the best-described molecules in medical research. As cancer is in most cases an age-related disease, it seems paradoxical that p53 is so strongly conserved from early multicellular organisms to humans. A function not directly related to tumor suppression, such as the regulation of metabolism in nontransformed cells, could explain this selective pressure. While this role of p53 in cellular metabolism is gradually emerging, it is imperative to dissect the tissue- and cell-specific actions of p53 and its downstream signaling pathways. In this review, we focus on studies reporting p53's impact on adipocyte development, function, and maintenance, as well as the causes and consequences of altered p53 levels in white and brown adipose tissue (AT) with respect to systemic energy homeostasis. While whole body

Hidalgo MR, Amadoz A, Çubuk C, et al.
Models of cell signaling uncover molecular mechanisms of high-risk neuroblastoma and predict disease outcome.
Biol Direct. 2018; 13(1):16 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.
RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.
CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.
REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.

Moghaddam Y, Andalib A, Mohammad-Ganji M, et al.
Evaluation of the effect of TIM-3 suppression by miR-498 and its effect on apoptosis and proliferation rate of HL-60 cell line.
Pathol Res Pract. 2018; 214(9):1482-1488 [PubMed] Related Publications
BACKGROUND: Acute Myeloid Leukemia (AML) is a Cancer of hematopoietic stem cells with a rapid progression. TIM-3 is expressed on leukemic stem cells (LSCs) in most types of AML and might have a positive effect on maintenance of malignant phenotype. MicroRNAs play important roles in either cancer progression or suppression. In this study were evaluated, the inhibitory effect of miR-498 on TIM-3 expression and its impact on proliferation and survival of HL-60 cell line.
METHODS: Firstly, the probable inhibitory effect of miR-498 on TIM-3 expression was predicted. HL-60 cells were cultured and expression of TIM-3 was induced on the cells using phorbol miristate acetate. The cells were transfected with miR-498 and expression level of TIM-3 were measured using with q-RT-PCR and flow cytometry methods. In addition, the effect of suppression of TIM-3 expression in HL-60 cell line was analyzed with apoptosis and cell proliferation assays.
RESULTS: Bioinformatics analyses predicted that miR-498 has high ability to silence TIM-3 gene expression. Our experiments confirmed that miR-498 was able to strongly silence TIM-3 expression (68% silencing) in HL-60 cell line (P < 0.002). Also, the cells with suppressed expression of TIM-3 had a lower proliferation and higher apoptosis rates.
CONCLUSION: Based on our results, the miR-498 can effectively suppress TIM-3 expression in the AML cell line. TIM-3 suppression, in turn, inhibits malignant cell proliferation and induces its apoptosis. Collectively, suppression of TIM-3 by miR-498 can be considered as a potential powerful way for treatment of AML.

Sasidharan Nair V, Toor SM, Taha RZ, et al.
DNA methylation and repressive histones in the promoters of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, PD-L1, and galectin-9 genes in human colorectal cancer.
Clin Epigenetics. 2018; 10(1):104 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed human malignancy worldwide. Upregulation of inhibitory immune checkpoints by tumor-infiltrating immune cells (TIICs) or their ligands by tumor cells leads to tumor evasion from host immunosurveillance. Changes in DNA methylation pattern and enrichment of methylated histone marks in the promoter regions could be major contributors to the upregulation of immune checkpoints (ICs) in the tumor microenvironment (TME).
METHODS: Relative expressions of various immune checkpoints and ligands in colon normal tissues (NT) and colorectal tumor tissues (TT) were assessed by qRT-PCR. The epigenetic modifications behind this upregulation were determined by investigating the CpG methylation status of their promoter regions using bisulfite sequencing. Distributions of histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) in promoter regions of these genes were assessed by chromatin immunoprecipitation (ChIP) assay.
RESULTS: We found that the expression levels of PD-1, CTLA-4, TIM-3, TIGIT, PD-L1, and galectin-9 were significantly higher in colorectal tumor tissues, compared with colon normal tissues. To study the role of DNA methylation, we checked the promoter CpG methylation of ICs and ligands and found that only CTLA-4 and TIGIT, among other genes, were significantly hypomethylated in TT compared with NT. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that bindings of H3K9me3 in PD-1 and TIGIT promoters and H3K27me3 in CTLA-4 promotor were significantly lower in TT compared with NT. Additionally, bindings of both H3K9me3 and H3K27me3 in the TIM-3 promoter were significantly lower in TT compared with NT.
CONCLUSION: This study shows that both DNA hypomethylation and H3K9me3 and H3K27me3 repressive histones are involved in upregulation of CTLA-4 and TIGIT genes. However, repressive histones, but not DNA hypomethylation, are involved in upregulation of PD-1 and TIM-3 genes in CRC tumor tissue. These epigenetic modifications could be utilized as diagnostic biomarkers for CRC.

Zhenjiang L, Rao M, Luo X, et al.
Cytokine Networks and Survivin Peptide-Specific Cellular Immune Responses Predict Improved Survival in Patients With Glioblastoma Multiforme.
EBioMedicine. 2018; 33:49-56 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
PURPOSE: We investigated serum cytokine and T-cell responses directed against tumour-associated antigens (TAAs) in association with survival of patients with glioblastoma multiforme (GBM).
PATIENTS AND METHODS: Peripheral blood from 205 treatment-naïve patients with glioma (GBM = 145; non-GBM = 60) was obtained on the day of surgery to measure (i) circulating T-cells reacting to viral antigens and TAAs, in the presence or absence of cytokine conditioning with IL-2/IL-15/IL-21 or IL-2/IL-7, and (ii) serum cytokine levels (IL-4, IL-5, IL-6, TNF-α, IFN-γ and IL-17A). Patients were followed-up for at least 1000 days post-surgery. Survivin protein and gene expression in resected GBM tumour tissue were confirmed by immunohistochemistry and real-time polymerase chain reaction, respectively. Antigen-specific T-cell responses were gauged by ICS (intracellular cytokine production). Associations between patient survival and immunological reactivity patterns were analysed using univariate and multivariate statistics.
RESULTS: Approximately 2% of patients with GBM and 18% of patients with non-GBM glioma, were alive beyond 1000 days of surgery. Univariate analysis indicated that the combination of three cytokines (IL-4/IL-5/IL-6, p = .0022; IFN-γ/TNF-α/IL-17A, p = .0083) but not a 'partial' combination of these cytokines, the IFN-γ immune response to EBV-EBNA-1 (p < .0001) as well as T-cell responses to the survivin
CONCLUSION: Serum cytokine patterns and lymphocyte reactivity to survivin

Sasidharan Nair V, El Salhat H, Taha RZ, et al.
DNA methylation and repressive H3K9 and H3K27 trimethylation in the promoter regions of PD-1, CTLA-4, TIM-3, LAG-3, TIGIT, and PD-L1 genes in human primary breast cancer.
Clin Epigenetics. 2018; 10:78 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Background: High expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and cancer progression. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints in cancer.
Methods: Expressions of different immune checkpoint genes and PD-L1 were assessed using qRT-PCR, and the underlying epigenetic modifications including CpG methylation and repressive histone abundance were determined using bisulfite sequencing, and histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 27 trimethylation (H3K27me3) chromatin immunoprecipitation assays (ChIP), respectively.
Results: We first assessed the expression level of six immune checkpoints/ligands and found that PD-1, CTLA-4, TIM-3, and LAG-3 were significantly upregulated in breast tumor tissues (TT), compared with breast normal tissues (NT). We investigated the epigenetic modifications beyond this upregulation in immune checkpoint genes. Interestingly, we found that CpG islands in the promoter regions of PD-1, CTLA-4, and TIM-3 were significantly hypomethylated in tumor compared with normal tissues. Additionally, CpG islands of PD-L1 promoter were completely demethylated (100%), LAG-3 were highly hypomethylated (80-90%), and TIGIT were poorly hypomethylated (20-30%), in both NT and TT. These demethylation findings are in accordance with the relative expression data that, out of all these genes, PD-L1 was highly expressed and completely demethylated and TIGIT was poorly expressed and hypermethylated in both NT and TT. Moreover, bindings of H3K9me3 and H3K27me3 were found to be reduced in the promoter loci of PD-1, CTLA-4, TIM-3, and LAG-3 in tumor tissues.
Conclusion: Our data demonstrate that both DNA and histone modifications are involved in upregulation of PD-1, CTLA-4, TIM-3, and LAG-3 in breast tumor tissue and these epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast cancer.

Tsilimigras DI, Ntanasis-Stathopoulos I, Bagante F, et al.
Clinical significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence.
Surg Oncol. 2018; 27(2):280-288 [PubMed] Related Publications
BACKGROUND: Hepatic resection is considered the optimal potentially curative treatment for colorectal liver metastases (CRLM). Following resection, up to two-thirds of patients will develop recurrence within 5-years. Genetic mutation analysis of CRLM, especially KRAS status, has been proposed as a means to guide treatment, as well as identifying patients who can derive the most survival benefit from hepatic resection.
METHODS: A systematic review of the literature was conducted the PubMed, Embase and Cochrane library through February 8th, 2018. The following algorithm was applied: "(colorectal OR rectal OR colon OR colonic) AND (liver OR hepatic) AND (metastasis OR metastases) AND (gene OR mutation OR KRAS OR BRAF OR SMAD4 OR RAS OR TP53 OR P53 OR APC OR PI3K OR MSI OR EGFR OR MACC1 OR microsatellite)."
RESULTS: From the 2404 records retrieved, 78 studies were finally deemed eligible; 47 studies reported mutational data on patients with resectable CRLM, whereas 31 studies reported on patients with unresectable CRLM. Mutational analyses were mostly performed on the CRLM specimen rather than the primary CRC. The vast majority of studies reported on the KRAS mutational status (88.5%, n = 69/78). Prevalence of KRAS mutations ranged from 25% to 52%. Most studies reported that RAS mutation was a negative prognostic factor for overall (OS) (n = 24) and recurrence-free (RFS) (n = 9) survival; a few reports noted no effect of RAS mutational status on OS (n = 4) or RFS (n = 6). Twelve studies reported on BRAF mutations with a prevalence of BRAF mutation ranging from 0 to 9.1% in resected CRLM specimens. BRAF mutation was strongly associated with a worse prognosis. TP53 and PIK3CA gene mutations did not affect long-term outcomes.
CONCLUSIONS: The biological status of each tumor provides the basis for individualized cancer therapeutics. Data on the mutational status on CRLM should be a part of multidisciplinary discussions to help inform the therapeutic approach, type of chemotherapy, as well as timing and approach of surgical resection.

Zhang C, Li F, Li J, et al.
Docetaxel Down-Regulates PD-1 Expression via STAT3 in T Lymphocytes.
Clin Lung Cancer. 2018; 19(5):e675-e683 [PubMed] Related Publications
BACKGROUND: Lung tumor is a major cause of cancer incidence and patient death. Chemotherapy is the primary therapy used to treat lung cancer. In addition to direct cytotoxic effect on tumor cells, chemotherapeutic drugs activate immune responses to exert antitumor function. Here, the effects of docetaxel on the inhibitory molecules, programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and T-cell immunoglobulin and mucin domain 3 (TIM-3) in T lymphocytes were explored in patients with lung adenocarcinoma.
PATIENTS AND METHODS: Peripheral blood mononuclear cells were isolated from lung adenocarcinoma patients receiving cisplatin-docetaxel chemotherapy. By flow cytometry and PCR, the expressions of CTLA-4, PD-1 and TIM-3 in T cell subsets were analyzed. Health subjects were used as control group.
RESULTS: During chemotherapy, suppressive markers were down-regulated in peripheral CD4
CONCLUSION: Our data support the hypothesis that chemotherapeutic drugs are not only purely cytotoxic but are also immune modulators.

Zahran AM, Mohammed Saleh MF, Sayed MM, et al.
Up-regulation of regulatory T cells, CD200 and TIM3 expression in cytogenetically normal acute myeloid leukemia.
Cancer Biomark. 2018; 22(3):587-595 [PubMed] Related Publications
BACKGROUND: The bone marrow immunosuppressive microenvironment of AML patients sustains and modulates proliferation, survival and drug resistance of AML through deregulation of both innate and adaptive immune response. We aimed to investigate the level of Tregs, expression of Tim-3 on peripheral blood T cells, expression of CD200 in myeloid blasts in newly diagnosed AML patients with normal cytogenetics (AML-NC) and their prognostic impact.
PATIENTS AND METHODS: This study included 40 patients with de novo AML-NC and 20 healthy controls. Flow-cytometry was used for detection of CD4+CD25+high FoxP3+ regulatory T cells, Tim-3 expression on peripheral blood T cells and CD200 expression on myeloid blasts.
RESULTS: The percentages of CD4+CD25+high and CD4+CD25+high Foxp3+ Tregs were significantly increased in AML patients than controls. The levels of Tregs, Tim-3/CD4+, Tim-3/CD8+, CD200 and MFI of CD200 were significantly lower in responding patients than in those with persistent leukemia. Only high CD200 expression (> 50%) showed statistically significant worse OS with P< 0.04.
CONCLUSION: The increased levels of Tregs, Tim-3 expression on peripheral blood T cells and CD200 expression in myeloid blast in AML patients could play a role in the development of AML. Analysis of these markers could serve as prognostic markers and might guide the therapy in AML patients in the future.

Hsu JM, Xia W, Hsu YH, et al.
STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion.
Nat Commun. 2018; 9(1):1908 [PubMed] Article available free on PMC after 01/02/2020 Related Publications
Enriched PD-L1 expression in cancer stem-like cells (CSCs) contributes to CSC immune evasion. However, the mechanisms underlying PD-L1 enrichment in CSCs remain unclear. Here, we demonstrate that epithelial-mesenchymal transition (EMT) enriches PD-L1 in CSCs by the EMT/β-catenin/STT3/PD-L1 signaling axis, in which EMT transcriptionally induces N-glycosyltransferase STT3 through β-catenin, and subsequent STT3-dependent PD-L1 N-glycosylation stabilizes and upregulates PD-L1. The axis is also utilized by the general cancer cell population, but it has much more profound effect on CSCs as EMT induces more STT3 in CSCs than in non-CSCs. We further identify a non-canonical mesenchymal-epithelial transition (MET) activity of etoposide, which suppresses the EMT/β-catenin/STT3/PD-L1 axis through TOP2B degradation-dependent nuclear β-catenin reduction, leading to PD-L1 downregulation of CSCs and non-CSCs and sensitization of cancer cells to anti-Tim-3 therapy. Together, our results link MET to PD-L1 stabilization through glycosylation regulation and reveal it as a potential strategy to enhance cancer immunotherapy efficacy.

Syring I, Weiten R, Müller T, et al.
The knockdown of the mediator complex subunit MED30 suppresses the proliferation and migration of renal cell carcinoma cells.
Ann Diagn Pathol. 2018; 34:18-26 [PubMed] Related Publications
BACKGROUND: The mediator complex consists of 33 subunits and plays a central role in transcription. Studies have already described the involvement of individual subunits, especially in carcinogenesis. With regard to the subunit MED30, this has, so far, only been confirmed in gastric and breast carcinoma. The role of MED30 in urological tumours is unknown.
MATERIALS AND METHODS: First, a database analysis using cBioPortal was performed for the mRNA expression and survival analysis of MED30 in clear cell renal cell carcinoma (ccRCC) and papillary RCC (pRCC). The immunohistochemical analysis (IHC) against MED30 was performed on tissue microarrays (TMA), with benign, ccRCC, pRCC samples, and ccRCC-metastases. Intensity evaluation was performed using the IRS (Immunoreactive Score). The ccRCC cell lines ACHN and A-498 were used for the functional investigation of proliferation, migration, and invasion after the knockdown of MED30 by siRNA.
RESULTS: In a database analysis by cBioPortal, it was shown that mRNA overexpression of MED30 in the pRCC was significantly associated with a poorer overall survival and progression-free survival. In the IHC, pRCC showed the highest level of MED30 expression, unfortunately without significant results in the survival analysis. The knockdown of MED30 resulted in a significant decrease in proliferation, migration, and invasion in ccRCC.
CONCLUSION: In summary, MED30 seems to be involved in the progression of the RCC.

Seo H, Kim BS, Bae EA, et al.
IL21 Therapy Combined with PD-1 and Tim-3 Blockade Provides Enhanced NK Cell Antitumor Activity against MHC Class I-Deficient Tumors.
Cancer Immunol Res. 2018; 6(6):685-695 [PubMed] Related Publications
Increased expression of coinhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I-deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti-PD-1/anti-Tim-3 treatment suppressed tumor progression in mice bearing MHC class I-deficient tumors, and the suppression was further enhanced by recombinant IL21 (rIL21) treatments through an NK-cell-dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I-deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I-low/deficient tumors.

Granier C, Vinatier E, Colin E, et al.
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells.
J Vis Exp. 2018; (132) [PubMed] Article available free on PMC after 08/02/2020 Related Publications
Immune cells are important components of the tumor microenvironment and influence tumor growth and evolution at all stages of carcinogenesis. Notably, it is now well established that the immune infiltrate in human tumors can correlate with prognosis and response to therapy. The analysis of the immune infiltrate in the tumor microenvironment has become a major challenge for the classification of patients and the response to treatment. The co-expression of inhibitory receptors such as Program Cell Death Protein 1 (PD1; also known as CD279), Cytotoxic T Lymphocyte Associated Protein 4 (CTLA-4), T-Cell Immunoglobulin and Mucin Containing Protein-3 (Tim-3; also known as CD366), and Lymphocyte Activation Gene 3 (Lag-3; also known as CD223), is a hallmark of T cell exhaustion. We developed a multiparametric in situ immunofluorescence staining to identify and quantify at the cellular level the co-expression of these inhibitory receptors. On a retrospective series of frozen tissue of renal cell carcinomas (RCC), using a fluorescence multispectral imaging technology coupled with an image analysis software, it was found that co-expression of PD-1 and Tim-3 on tumor infiltrating CD8

Perera-Bel J, Hutter B, Heining C, et al.
From somatic variants towards precision oncology: Evidence-driven reporting of treatment options in molecular tumor boards.
Genome Med. 2018; 10(1):18 [PubMed] Article available free on PMC after 08/02/2020 Related Publications
BACKGROUND: A comprehensive understanding of cancer has been furthered with technological improvements and decreasing costs of next-generation sequencing (NGS). However, the complexity of interpreting genomic data is hindering the implementation of high-throughput technologies in the clinical context: increasing evidence on gene-drug interactions complicates the task of assigning clinical significance to genomic variants.
METHODS: Here we present a method that automatically matches patient-specific genomic alterations to treatment options. The method relies entirely on public knowledge of somatic variants with predictive evidence on drug response. The output report is aimed at supporting clinicians in the task of finding the clinical meaning of genomic variants. We applied the method to 1) The Cancer Genome Atlas (TCGA) and Genomics Evidence Neoplasia Information Exchange (GENIE) cohorts and 2) 11 patients from the NCT MASTER trial whose treatment discussions included information on their genomic profiles.
RESULTS: Our reporting strategy showed a substantial number of patients with actionable variants in the analyses of TCGA and GENIE samples. Notably, it was able to reproduce experts' treatment suggestions in a retrospective study of 11 patients from the NCT MASTER trial. Our results establish a proof of concept for comprehensive, evidence-based reports as a supporting tool for discussing treatment options in tumor boards.
CONCLUSIONS: We believe that a standardized method to report actionable somatic variants will smooth the incorporation of NGS in the clinical context. We anticipate that tools like the one we present here will become essential in summarizing for clinicians the growing evidence in the field of precision medicine. The R code of the presented method is provided in Additional file 6 and available at .

Zhao X, Zhao L, Yang H, et al.
Pyruvate kinase M2 interacts with nuclear sterol regulatory element-binding protein 1a and thereby activates lipogenesis and cell proliferation in hepatocellular carcinoma.
J Biol Chem. 2018; 293(17):6623-6634 [PubMed] Article available free on PMC after 08/02/2020 Related Publications
Dysregulation of lipid metabolism is common in cancer cells, but the underlying mechanisms are poorly understood. Sterol regulatory element-binding proteins (SREBPs) stimulate lipid biosynthesis through transcriptional activation of lipogenic enzymes. However, SREBPs' roles and potential interacting partners in cancer cells are not fully defined. Using a biochemical approach, we found here that pyruvate kinase M2 (PKM2) physically interacts with the nuclear form of SREBP-1a (nBP1a), by binding to amino acids 43-56 in nBP1a. We also found that PKM2 activates SREBP target gene expression and lipid biosynthesis by stabilizing nBP1a proteins. Using a competitive peptide inhibitor to block the formation of the SREBP-1a/PKM2 complex, we observed that this blockade inhibited lipogenic gene expression. Of note, nBP1a phosphorylation at Thr-59 enhanced the binding to PKM2 and promoted cancer cell growth. Moreover, we show that PKM2 phosphorylates Thr-59

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