Different Types Of Human Tumors Research Articles

Integrative analysis revealed a correlation of PIAS family genes expression with prognosis, immunomodulation and chemotherapy

BackgroundProtein inhibitor of activated STATs (PIAS) has pleiotropic biological effects, such as protein post-translational modification, transcriptional coregulation and gene editing. It is reported that PIAS family genes are also correlated with immune cells infiltration in cancers that highlights their unnoticed biological role in tumor progression. However, the relationship of their expression with prognosis, immune cell infiltration, tumor microenvironment, and immunotherapy in pan-cancer has been rarely reported.MethodsThe multi-omics data were used to investigate the expression level of PIAS family members in pan-cancer, and the prognostic value of their expression in different tumors was analyzed by univariate Cox regression and Kaplan–Meier. Correlation analysis was used to investigate the relationship of PIAS gene expression with tumor microenvironment, immune infiltrating subtypes, stemness score and drug sensitivity. In addition, we also used wound healing and transwell assays to verify the biological effects of PIAS family gene expression on invasion and metastasis of HCC cells.ResultsWe found that PIAS family genes expression is significantly heterogeneous in tumors by multi-genomic analysis, and associated with poor prognosis in patients with multiple types of cancer. Furthermore, we also found that genetic alterations of PIAS family genes were not only common in different types of human tumors, but were also significantly associated with disease-free survival (DFS) across pan-cancer. Single-cell analysis revealed that PIAS family genes were mainly distributed in monocytes/macrophages. Additionally, we also found that their expression was associated with tumor microenvironment (including stromal cells and immune cells) and stemness score (DNAss and RNAss). Drug sensitivity analysis showed that PIAS family genes were able to predict the response to chemotherapy and immunotherapy. PIAS family genes expression is closely related to tumor metastasis, especially PIAS3. High PIAS3 expression significantly promotes the migration and invasion of liver cancer cell lines (HCC-LM3 and MHCC97-H).ConclusionsTaking together, these findings contribute to determine whether the PIAS family genes are a potential oncogenic target gene, which have important contribution for the development of cancer immunotherapy.

APOB is a potential prognostic biomarker in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is significantly associated with adverse prognostic outcomes. The development and progression of different types of human tumors are significantly influenced by APOB. Nevertheless, the significance and pathomechanisms of APOB in HCC have not been conclusively determined. We assessed APOB expression levels in HCC using three publicly available databases of TIMER2.0, UALCAN and Human Protein Atlas. To identify the biological function of APOB, we conducted enrichment analysis via LinkedOmics. Moreover, UALCAN was employed to assess the relationship between APOB expression and clinicopathological features among HCC patients. Additionally, the Kaplan–Meier plotter was utilized to investigate the prognostic relevance of APOB in HCC. To explore potential regulatory ncRNAs that could bind to APOB, we utilized StarBase and GEPIA. Furthermore, the correlation between APOB expression and immune cell infiltration, as well as immune checkpoint genes, was investigated using Spearman's correlation analysis in TISIDB, GEPIA, and TIMER2.0. The findings of our investigation showed a notable decrease in the expression levels of APOB among individuals diagnosed with HCC. Moreover, a noteworthy correlation was observed between the expression of APOB and immune checkpoint genes, alongside the occurrence of immune cell infiltration. The levels of APOB expression in HCC tissues also showed correlations with various clinicopathological features. According to Cox regression analysis, decreased APOB expression emerged as a potential autonomous predictor for OS, RFS, DSS, and PFS among HCC patients. Furthermore, we identified six potential pathways associated with non-coding RNA (ncRNA) as the most promising pathway for APOB in HCC. Our results illuminate the possible involvement of APOB in HCC and offer understanding into its governing mechanisms and medical importance.

A pan-cancer analysis of TNFAIP8L1 in human tumors.

TNFAIP8L1, as a recently identified member in TNFAIP8 family, plays an important role in tumorigenesis. However, a pan-cancer analysis of TNFAIP8L1 in human tumors has not been conducted until now. The main purpose of study is to investigate TNFAIP8L1 during 33 different types of human tumors by using TCGA and GTEx. The pan-cancer analysis showed that TNFAIP8L1 was significantly over-expressed in 15 cancers and low-expressed in 9 cancers. There were distinct relations between TNFAIP8L1 expression and prognosis of patients with cancer. Furthermore, we also found that DNA methylation and RNA modification of TNFAIP8L1 were associated with many cancers. And then, we detected that TNFAIP8L1 level was positively associated with cancer-associated fibroblasts (CAFs) in many tumors. And, we obtained that TNFAIP8L1 expression was related with most of immune inhibitory and stimulatory genes in multiple types of tumors. We also found TNFAIP8L1 expression was correlated with most of chemokine, receptor, MHC, immunoinhibitor and immunostimulator gens in most of cancers. Moreover, we detected TNFAIP8L1 expression was associated with TMB and MSI in several tumors. Finally, TNFAIP8L1 gene had a significant positive association with 5 genes including BCL6B, DLL4, PCDH12, COL4A1 and DLL4 in the majority of tumors. GO enrichment and KEGG pathway analyses showed that TNFAIP8L1 in thepathogenesis of cancer may be related to "purine nucleoside binding," "purine ribonucleoside binding," "ECM-receptor interaction," etc. Our first pan-cancer study may provide a deep comprehending of TNFAIP8L1 in tumoeigenesis from different tumors.

Abstract SY41-02: Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells

Abstract We have recently identified the cells uniquely responsible for the formation of metastasis in different types of human tumors. These cells have intriguing characteristics: i) they form primary lesions as efficiently as their tumor-initiating counterparts, but are exclusive in their ability to generate metastases; ii) they express the fatty acid translocase CD36, and are characterized by a unique lipid metabolic signature; iii) they are exquisitely sensitive to the levels of fat in circulation, and consequently, they relate the predisposition of metastasis directly to the content of dietary fat; iv) they are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential in preclinical models. In my talk, I will present our latest data on the molecular characterization of metastatic-initiating cells. I will place special emphasis showing how specific dietary lipids exert a striking long-term epigenetic effect over metastatic-initiating cells related to activation of intra-tumor Schwann cells, putting forward a novel concept of ¨metastatic epigenetic memory¨ elicited by our diet. Citation Format: Salvador Aznar-Benitah. Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY41-02.

Identification of oxazolo[4,5-g]quinazolin-2(1H)-one Derivatives as EGFR Inhibitors for Cancer Prevention.

Objective:Abnormal expression of EGFR (epidermal growth factor receptor) results in different types of human tumors. Quinazoline-containing derivative signify an attractive platform for EGFR inhibitors. The present study aims to discover the potential binders of a group of compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative as EGFR inhibitors. Methods:We apply multiple computational procedures, including pharmacophore-based virtual screening methods, to perform a preliminary screening against EGFR over compounds belonging to oxazolo[4,5-g]quinazoline-2(1H)-one derivative. Then, we carried a fine screening by molecular dynamics simulations, followed by free energy calculations. Results:The best pharmacophore model created has five characteristics. Three hydrogen bonds acceptors (A) and two aromatic rings (R) make up AAARR (a sequential representation of chemical features of ligands). We have performed pharmacophore-based screening with different databases like Asinex, Chembridge, Lifechemicals, Maybridge, Specs, and Zinc. Top-scoring 30 molecules were considered for performing induced fit docking. Molecular Dynamics Simulations executed for the top five ligands confirmed that throughout the simulation, the protein-ligand complexes remained stable. Conclusion: Thus, the results obtained from this research provide insights for the development of oxazolo[4,5-g]quinazoline-2(1H)-one derivative as potent EGFR inhibitors.

Computational investigation of adenosine 5′-(α,β-methylene)-diphosphate (AMPCP) derivatives as ecto-5′-nucleotidase (CD73) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

CD73, as a surface enzyme anchored on the outside of the cell membrane via glycosylphosphatidylinositol (GPI), can convert the AMP in the tumor cell microenvironment into adenosine to promote the growth of tumor cells. It has been overexpressed in many different types of human tumors, such as gastric cancer, pancreatic cancer, liver cancer, and other tumor cells. Therefore, targeted inhibitors of CD73 are considered potential tumor treatment methods. Due to the low bioavailability of nucleoside CD73 inhibitors, it is necessary to develop new inhibitors. In this study, through molecular docking, three-dimensional quantitative structure–activity relationship (3D-QSAR) and molecular dynamics (MD) simulations, a series of CD73 inhibitors were calculated and studied to reveal their structure–activity relationships. Through molecular docking studies, the possible mode of interaction between inhibitors and protein is explored. Subsequently, a 3D-QSAR model was established by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values are 0.708 and 0.983, respectively, while for the best CoMSIA model, the Q2 and R2 values are 0.809 and 0.992, respectively. Based on the contour maps, we designed ten new CD73 inhibitors and predicted their activity by the model, all of them are better than molecules in the dataset. In addition, in order to select potential drug candidates, ADMET prediction was performed on template molecules and designed compounds. Moreover, the stability of the complex formed by the two inhibitors and CD73 was evaluated by molecular dynamics simulation, and the results are consistent with the results of molecular docking and 3D-QSAR research. Finally, the binding free energy was calculated by the surface area method (MM-GBSA), and the results are consistent with the activities that van der Waals and Coulomb contribute the most during the binding process of the molecule to the CD73 protein. In conclusion, our research provides valuable information for the further development of CD73 inhibitors.

Ligand-based design approach of potential Bcl-2 inhibitors for cancer chemotherapy

Background and ObjectivesOverexpression of prosurvival Bcl-2 family members make tumor cells resistant to conventional cancer therapeutic agents. It is commonly observed feature in many different types of human tumors. Hence, small-molecules as Bcl-2 inhibitors may have a promising therapeutic potential for the treatment of human cancer. The given study focusses on development of novel and small Bcl-2 inhibitors using ligand-based drug design approach. MethodsLigand based pharmacophore was generated using the PHASE tool of Schrödinger and screened ZINC database through ZINCPharmer webserver to identify compounds with similar features. Compounds having good fitness score were selected for molecular docking and binding interactions were compared with drugs in market as well as trials. QSAR model was generated using advanced AutoQSAR tool and validated for prediction of unknown compounds. QSAR prediction of in silico active identified three potential compounds and were subjected to investigate stability by molecular dynamics simulations and MM-PBSA binding energy calculations. ResultsStudy identified three in silico potential molecules with good stability and binding affinity. Further substructure search and pIC50 value prediction has identified six more molecules. Total nine molecules have demonstrated good drug likeness features. ConclusionFinal oral rat LD50 calculation of nine molecules has identified three hit molecules i.e., ZINC76760927, ZINC76768675 and ZINC52767796 for further in vitro and in vivo testing as safe and potential Bcl-2 inhibitors.

USP18-deficiency in cervical carcinoma is crucial for the malignant behavior of tumor cells in an ERK signal-dependent manner.

Ubiquitin-specific peptidase (USP)18 belongs to the USP family, and is involved in cleaving and removing ubiquitin or ubiquitin-like molecules from their target molecules. Recently, increasing evidence has suggested that USP18 is constitutively expressed in different types of human tumors, and ectopic expression or downregulation of USP18 expression may contribute to tumorigenesis. However, the role of USP18 in uterine cervical cancer (UCC) remains unclear. Thus, the present study aimed to investigate USP18 expression in a human tissue microarray constructed using UCC and non-cancer cervical tissues, and to determine the potential role and molecular mechanism by which USP18 is implicated in the tumor biology of human UCC HeLa cells. Microarray analysis demonstrated that USP18 protein expression was downregulated in tumor tissues compared with in normal tissues. In addition, in vitro analysis revealed that USP18-knockdown markedly promoted the proliferation, colony formation, migration and aggressiveness of HeLa cells. Mechanistic analysis demonstrated that USP18-knockdown increased the levels of Bcl-2, STAT3 and phosphorylated-ERK in HeLa cells. Notably, USP18 silencing-induced malignant phenotypes were interrupted following exogenous administration of the ERK1/2 inhibitor PD98059. Overall, the results of the present study suggested that USP18 may be a potent inhibitor involved in UCC tumor-associated biological behaviors, which are associated with the ERK signaling pathway.

Construction of in vitro patient-derived tumor models to evaluate anticancer agents and cancer immunotherapy.

An in vitro assay system using patient-derived tumor models represents a promising preclinical cancer model that replicates the disease better than traditional cell culture models. Patient-derived tumor organoid (PDO) and patient-derived tumor xenograft (PDX) models have been previously established from different types of human tumors to recapitulate accurately and efficiently their tissue architecture and function. However, these models have low throughput and are challenging to construct. Thus, the present study aimed to establish a simple in vitro high-throughput assay system using PDO and PDX models. Furthermore, the current study aimed to evaluate different classes of anticancer drugs, including chemotherapeutic, molecular targeted and antibody drugs, using PDO and PDX models. First, an in vitro high-throughput assay system was constructed using PDO and PDX established from solid and hematopoietic tumors cultured in 384-well plates to evaluate anticancer agents. In addition, an in vitro evaluation system of the immune response was developed using PDO and PDX. Novel cancer immunotherapeutic agents with marked efficacy have been used against various types of tumor. Thus, there is an urgent need for in vitro functional potency assays that can simulate the complex interaction of immune cells with tumor cells and can rapidly test the efficacy of different immunotherapies or antibody drugs. An evaluation system for the antibody-dependent cellular cytotoxic activity of anti-epidermal growth factor receptor antibody and the cytotoxic activity of activated lymphocytes, such as cytotoxic T lymphocytes and natural killer cells, was constructed. Moreover, immune response assay systems with bispecific T-cell engagers were developed using effector cells. The present results demonstrated that in vitro assay systems using PDO and PDX may be suitable for evaluating anticancer agents and immunotherapy potency with high reproducibility and simplicity.

Computational investigation of 4,5-diphenyl-1H-pyrrole-3-carboxylic acid derivatives as B-cell lymphoma-extra large (Bcl-xL) inhibitors by using 3D-QSAR, molecular docking, and molecular dynamics simulations

B-cell lymphoma-extra large (Bcl-xL) can inhibit apoptosis via heterodimerization with pro-apoptotic Bcl-2 family proteins, and is over-expressed in many different types of human tumors and has been regarded as a novel cancer therapeutic strategy. Due to the fact that current Bcl-xl inhibitors lack sustained effectiveness and the occurrence of some unpredictable side effects, the development of new inhibitors is necessary. In this study, computational study was applied to a series of Bcl-xL inhibitors to reveal the relationship between structure and activities through applying molecular docking, three-dimensional qualitative structure-activity relationship (3D-QSAR), and molecular dynamic (MD) simulations. A molecular docking study was performed to explore possible modes of action between inhibitors and Bcl-xL protein. Subsequently, 3D-QSAR models were generated with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values were computed as 0.927 and 0.999, while those were computed as 0.943 and 0.998 for the best CoMSIA model. Twenty new Bcl-xL inhibitors were designed, and all their predictive activities were improved than molecules in the dataset based on the contour maps. In addition, MD simulations were conducted to evaluate the stability of the complexes conformed by two inhibitors and Bcl-xL, and the results were consistent with those of the molecular docking and 3D-QSAR studies. Finally, binding free energy was computed through molecular mechanics performed by surface area approach (MM-GBSA), and the result congruent with the activities which indicated van der Waals as well as lipophilic energy contributing the most during the molecular with Bcl-xL protein binding. In brief, our research provided valuable information for further development of Bcl-xL inhibitors.

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors.

Insulin-like growth factor 1 (IGF1) is a key regulator of tissue growth and development that is also implicated in the initiation and progression of various cancers. The human IGF1 gene contains six exons and five long introns, the transcription of which is controlled by two promoters (P1 and P2). Alternate promoter usage, as well as alternative splicing (AS) of IGF1, results in the expression of six various variants (isoforms) of mRNA, i.e., IA, IB, IC, IIA, IIB, and IIC. A mature 70-kDa IGF1 protein is coded only by exons 3 and 4, while exons 5 and 6 are alternatively spliced code for the three C-terminal E peptides: Ea (exon 6), Eb (exon 5), and Ec (fragments of exons 5 and 6). The most abundant of those transcripts is IGF1Ea, followed by IGF1Eb and IGF1Ec (also known as mechano-growth factor, MGF). The presence of different IGF1 transcripts suggests tissue-specific auto- and/or paracrine action, as well as separate regulation of both of these gene promoters. In physiology, the role of different IGF1 mRNA isoforms and pro-peptides is best recognized in skeletal muscle tissue. Their functions include the development and regeneration of muscles, as well as maintenance of proper muscle mass. In turn, in nervous tissue, a neuroprotective function of short peptides, produced as a result of IGF1 expression and characterized by significant blood-brain barrier penetrance, has been described and could be a potential therapeutic target. When it comes to the regulation of carcinogenesis, the potential biological role of different var iants of IGF1 mRNAs and pro-peptides is also intensively studied. This review highlights the role of IGF1 isoform expression (mRNAs, proteins) in physiology and different types of human tumors (e.g., breast cancer, cervical cancer, colorectal cancer, osteosarcoma, prostate and thyroid cancers), as well as mechanisms of IGF1 spliced variants involvement in tumor biology.

Abstract 6128: Evaluation of therapeutic efficacy of combination of 4HPR and SAHA for inhibition of growth of human glioblastoma T98G xenografts in zebrafish

Abstract Glioblastoma is the most aggressive and deadly primary brain cancer in humans. Despite the current treatments using surgery, radiotherapy, and chemotherapy, glioblastoma reappears due to drug resistance. New approaches for treatment of glioblastoma suggest that combination of two drugs may overcome the drug resistance. In this study, we have evaluated the efficacy of the combination of N-(4-hydroxphenyl) retinamide (4HPR) and suberoylanilide hydroxamic acid (SAHA) for inhibition of human glioblastoma T98G cells in a zebrafish xenograft model in our laboratory. Both 4HPR and SAHA have been approved by the United States Food and Drug Administration for treatment of cancers in the clinics. The synthetic retinoid 4HPR works via retinoic acid receptor signaling pathways to inhibit cancer cell proliferation and induce apoptosis, while SAHA is a histone deacetylase (HDAC) inhibitor that targets class I, II, and IV HDACs for controlling growth of cancer cells. Although rodent models have provided valuable insights into the biology and pathology of glioblastoma, these models are frankly unsuitable and increasingly unaffordable for high-throughput screening and profiling of novel therapeutic agents for rapid translation to the clinics. The optical transparency of zebrafish embryos and larvae provides the unique opportunity to track tumors in a way that is impossible in rodent models. Small size of zebrafish embryos allows for study design in small plates, making them a more useful laboratory system than other cancer models. Zebrafish lack a fully functioning adaptive immune response until 4 days post-fertilization, allowing rejection-free xenografts of human tumors during this period. Recently, zebrafish xenograft models have emerged as a new powerful tool for studying different types of human tumors including glioblastoma and for evaluating therapeutic efficacy of different drugs alone and in combination. Organ systems and cell types are common in human and zebrafish. Tumors that occur in the same organs in human and zebrafish look and behave alike, often share common genetic makeups, and employ basic mechanisms for tumor formation, expansion, and spread. Zebrafish xenograft model of human glioblastoma offers us a major opportunity for discovering key pathways of this tumor growth and for evaluating efficacy of a novel combination therapy. We loaded exponentially grown T98G cells labeled with CellTrace™ Red into the glass needle (0.75 mm internal diameter without filament, World Precision Instruments, FL) at a density of about 1 × 106 cells/200 µl. Using a micro-injector, each anesthetized zebrafish larva was microinjected with about 100 T98G cells into the duct of Cuvier at 1.5 - 3.0 psi. After injection, larvae were transferred to fresh egg water for recovery during 1 h at 28 ± 0.5°C and then incubated at 33°C for the rest of the experiment. After 2 days of tumor growth, we treated zebrafish larvae with 4 µM 4HPR and 8 µM SAHA alone and in combination and incubated for 3 days. Results showed that 4HPR and SAHA alone inhibited growth of T98G xenografts in zebrafish, but the combination of the two drugs most significantly reduced T98G cell proliferation inside of the zebrafish. Our work suggested that the zebrafish xenograft model could be useful to identify the therapeutic efficacy of combination of drugs in the treatment of glioblastoma. Citation Format: Firas Khathayer, Katie L. Kathrein, Mitzi Nagarkatti, Swapan K. Ray. Evaluation of therapeutic efficacy of combination of 4HPR and SAHA for inhibition of growth of human glioblastoma T98G xenografts in zebrafish [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6128.

The entry of nanoparticles into solid tumours.

The concept of nanoparticle transport through gaps between endothelial cells (inter-endothelial gaps) in the tumour blood vessel is a central paradigm in cancer nanomedicine. The size of these gaps was found to be up to 2,000 nm. This justified the development of nanoparticles to treat solid tumours as their size is small enough to extravasate and access the tumour microenvironment. Here we show that these inter-endothelial gaps are not responsible for the transport of nanoparticles into solid tumours. Instead, we found that up to 97% of nanoparticles enter tumours using an active process through endothelial cells. This result is derived from analysis of four different mouse models, three different types of human tumours, mathematical simulation and modelling, and two different types of imaging techniques. These results challenge our current rationale for developing cancer nanomedicine and suggest that understanding these active pathways will unlock strategies to enhance tumour accumulation.

The microcosmos of intratumor heterogeneity: the space-time of cancer evolution.

The Cancer Genome Atlas consortium brought us terabytes of information about genetic alterations in different types of human tumors. While many cancer-driver genes have been identified through these efforts, interrogating cancer genomes has also shed new light on tumor complexity. Mutations were found to vary tremendously in their allelic frequencies within the same tumor. Based on those variant allelic frequencies grouping, an estimate of genetically distinct "clones" of cancer cells can be determined for each tumor. It was estimated that 4-8 clones are present in every human tumor. Presence of distinct clones, cells that differ in their genotype and/or phenotype, is one of the roots for the major challenge of effectively curing cancer patients. Any given treatment applied to a heterogeneous mixture of cancer cells will yield distinct responses in different cells and may be ineffective in killing particular clones. Moreover, in highly heterogeneous tumors, stochastically, there is a higher chance of presence of traits, such as point mutations in key receptor tyrosine kinases, that drive drug resistance. Thus, intratumor heterogeneity is like an arsenal, providing a variety of weapons for self-defense against cancer-targeted therapy. However, in this arsenal the supplies are constantly changing, as cancer cells are accumulating new mutations. What is also changing is the battlefield-the tumor microenvironment including all noncancerous cells within the tumor and surrounding tissue, which also contribute to the diversification of cancer's forces. In order to design more effective therapies that would target this ever-changing landscape, we need to learn more about the two elusive variables that shape the tumor ecosystem: the space-how could we exploit the organization of tumor microenvironment? and the time-how could we predict the changes in heterogeneous tumors?

Guanine Content of MicroRNAs is Associated with their Tumor- Suppressive and Oncogenic Roles in Lung and Breast Cancers.

microRNAs (miRNAs, miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level and fine-tune gene functions. Global repression of miRNAs expression in different types of human tumors, after exposure to cigarette smoke, or to the hormone estrogen, have been shown to be associated with guanine (G) enrichment in the terminal Loops (TLs) of their precursors. We integrated the G content of miRNA mature forms and precursor miRNA TLs with their described function in the literature, using the PubMed database. Gene Ontology term analysis was used to describe the pathways in which the G-enriched miRNA targets are involved. Herein, we show an association between the relative G enrichment of precursor miRNAs' TLs and their tendency to act as tumor suppressor miRs in human lung and breast cancers. Another association was observed between the high G content of the miRNAs 5-mature forms and their tendency to act as oncomiRs. The results support previous findings showing that the G sequence content is an important feature determining miRNA expression and function, and opens the way for future cancer investigations in this direction.

Synthesis and cytotoxic activity of 3-amino substituted fusidane triterpenoids

New 3-amino substituted derivatives, containing linear, aromatic, and heterocyclic fragments, as well as conjugates with biogenic amines—spermine and spermidine, were synthesized from 3,11-dioxo analogs of fusidic acid and its methyl ester. Antitumor activity of the compounds was studied in vitro towards the 60 cell lines of nine different types of human tumors of the NCI collection. Introduction of pyrrolidine, n-butylamine, benzylamine, and ethylenediamine substituents into the molecules were found to provide a pronounced selective effect on five cell lines of leukemia: HL-60, K-562, MOLT-4, RPMI-8226, and SR, inhibiting their growth from 70% to complete death of cancer cells. Methylfusidate derivative with a spermine fragment was shown to exhibit the widest spectrum of antiproliferative action among the obtained compounds, inhibiting the growth of leukemia, NSC lung cancer, colon cancer, and melanoma cell lines of 68–92%.

PICOT binding to chromatin-associated EED negatively regulates cyclin D2 expression by increasing H3K27me3 at the CCND2 gene promoter

Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3 (Grx3; Glrx3)) is a ubiquitous protein that can interact with the embryonic ectoderm development (EED) protein via each of its two C-terminal PICOT/Grx homology domains. Since EED is a Polycomb-Group protein and a core component of the polycomb repressive complex 2 (PRC2), we tested the involvement of PICOT in the regulation of PRC2-mediated H3 lysine 27 trimethylation (H3K27me3), transcription and translation of selected PRC2 target genes. A fraction of the cellular PICOT protein was found in the nuclei of leukemia cell lines, where it was associated with the chromatin. In addition, PICOT coimmunoprecipitated with chromatin-residing EED derived from Jurkat and COS-7 cell nuclei. PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter. In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression. Since elevated expression levels of PICOT were reported in several different tumors and correlated in the current studies with decreased transcription and translation of the CCND2 gene, we tested whether this opposite correlation exists in human cancers. Data from the Cancer Genome Atlas (TCGA) database indicated statistically significant negative correlation between PICOT and CCND2 in eight different human tumors where the highest correlation was in lung (p = 8.67E−10) and pancreatic (p = 1.06E−5) adenocarcinoma. Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors. The results suggest that PICOT binding to chromatin-associated EED modulates the H3K27me3 level at the CCND2 gene promoter which may be one of the potential mechanisms for regulation of cyclin D2 expression in tumors. These findings also indicate that a low PICOT/CCND2 expression ratio might serve as a good predictor of patient survival in selected human cancers.

Role of Interleukin17F (IL17F) Gene Polymorphism in Susceptibility to Acute Myeloid Leukemia

Th17 cells (subset of CD4+ cells) are characterized by interleukin (IL)-17A and IL-17F production, which share strong homology, and surface expression of the IL-23 receptor (IL-23R). They have been implicated in the pathogenesis of inflammatory, autoimmune diseases and in many different types of human tumors, including lymphoma and myeloma. Objectives: The aim of this study was to determine the association between the polymorphic features located within the IL-17A, IL-17F and IL-23R genes and susceptibility to or association with AML and the relationship between these polymorphic variants and the plasma IL-17 levels in all studied groups. Subjects and Methods: 82 individual of Egyptian population including 27 AML patients, 40 individual who are relatives of those patients and 15 apparently healthy controls. All were subjected to detection of Interleukin 17F gene polymorphism by 2 steps: first Conventional Polymerase Chain Reaction then Restriction Fragment length Polymorphism by Restriction enzymeHIN1II (NLAIII) (PCR-RFLP) assay, Detection of Interleukin 17A and Interleukin23 receptor genetic polymorphisms by real time Polymerase Chain Reaction and Quantification of Interleukin 17 gene protein product by Enzyme Linked Immunosorbent Assay (ELISA). Results: our results revealed that the (G) variant of IL17F and its homozygosity were significantly higher among patients compared to relatives and healthy individual. While IL17-A and IL23-R polymorphisms elicit non statistical significant difference among the three groups. Also a significant correlation was observed between IL17 protein plasma level and the three polymorphisms (IL17F, IL17A and IL23R genetic polymorphisms). Conclusions: IL-17F gene G single mutant and GG homozygous mutant were associated with acute myeloid leukemia susceptibility in Egyptian population while IL17-A and IL23-R polymorphisms were not associated with susceptibility to the disease. Also there were statistical significant association (P˂0.05) and high statistical significant (P˂0.001) association between ELISA (IL17 plasma level) results and the three genetic polymorphisms in studied groups. There was high statistical significant difference (P˂0.001) between patients and other two groups in IL17 plasma level by ELISA.

Where to "cut-off"?

Where to "cut-off"?

A pan-cancer study of the transcriptional regulation of uricogenesis in human tumours: pathological and pharmacological correlates.

Uric acid (UA) is the end product of the catabolism of purines, and its serum levels are commonly increased in cancer patients. We aimed to explore the transcriptional regulation of tumour uricogenesis in human tumours, and relate uricogenesis with tumour pathological and pharmacological findings. Using data from The Cancer Genome Atlas (TCGA), we analysed the expression levels of xanthine dehydrogenase (XDH) and adenine phosphoribosyltransferase (APRT), two key enzymes in UA production and the purine salvage pathway, respectively. We found large differences between tumour types and individual tumours in their expression of XDH and APRT. Variations in locus-specific DNA methylation and gene copy number correlated with the expression levels of XDH and APRT in human tumours respectively. We explored the consequences of this differential regulation of uricogenesis. Tumours with high levels of XDH mRNA were characterised by higher expression of several genes encoding pro-inflammatory and immune cytokines, and increased levels of tumour infiltration with immune cells. Finally, we studied cancer drug sensitivity using data from the National Cancer Institute-60 (NCI-60) database. A specific correlation was found between the expression levels of APRT and cell sensitivity to the chemotherapeutic agent 5-fluorouracil (5-FU). Our findings underline the existence of great differences in uricogenesis between different types of human tumours. The study of uricogenesis offers promising perspectives for the identification of clinically relevant molecular biomarkers and for tumour stratification in the therapeutic context.