Implications For Carcinogenesis Research Articles

Gut microbiota and epigenetics in colorectal cancer: implications for carcinogenesis and therapeutic intervention.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. The occurrence of CRC is associated with various genetic and epigenetic mutations in intestinal epithelial cells that transform them into adenocarcinomas. There is increasing evidenceindicating thegut microbiota playsa crucial role in the regulation of host physiological processes. Alterations in gut microbiota composition are responsible for initiating carcinogenesis through diverse epigenetic modifications, including histone modifications, ncRNAs and DNA methylation. This work was designedto comprehensively reviewrecent findings to provide insight into the associations between the gut microbiota and CRC at an epigenetic level. These scientific insights can be used in the future to develop effective strategies for early detection and treatment of CRC.

Expression of mast cell tryptase and immunoglobulin E is increased in cutaneous photodamage: implications for carcinogenesis

Purpose: Mast cells, their serine proteinase tryptase, and immunoglobulin E (IgE) can be involved in cutaneous carcinogenesis. Materials and methods: To study the association of tryptase+ and IgE+ cells with photodamage and skin cancers 385 adult patients (201 males, 184 females, 75 with immunosuppression) at risk of any type of skin cancer were examined. Skin biopsies were taken from the sun-protected medial arm and from the photodamaged dorsal forearm skin followed by immunohistochemical staining for tryptase and IgE. Results: The results show that tryptase+ and IgE+ cells are significantly higher in number in the photodamaged than sun-protected skin, both in immunocompetent and -compromised subjects, and there is a strong correlation between tryptase+ and IgE+ cells. The numbers of forearm tryptase+ and especially IgE+ cells associated significantly with the forearm photodamage severity. In the logistic regression analysis, the forearm to upper arm ratio of IgE+ cells produced a univariate odds ratio of 1.521 (p = .010) and a multivariate one of 3.875 (p = .047) for the history of squamous cell carcinoma. The serum level of total IgE correlated significantly to the IgE to tryptase ratio in both skin sites. Conclusions: Therefore, IgE+ mast cells participate in photodamage and carcinogenesis, though it is unclear whether they are tumor-protective or -causative.

Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future.

The flavoenzyme N-ribosyldihydronicotinamide (NRH):quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids. NQO2 may play important roles that go beyond quinone metabolism and include the regulation of oxidative stress, inflammation, and autophagy, with implications in carcinogenesis and neurodegeneration. NQO2 is a highly polymorphic gene with several allelic variants, including insertions (I), deletions (D) and single-nucleotide (SNP) polymorphisms located mainly in the promoter, but also in other regulatory regions and exons. This is the first systematic review of the literature reporting on NQO2 gene variants as risk factors in degenerative diseases or drug adverse effects. In particular, hypomorphic 29 bp I alleles have been linked to breast and other solid cancer susceptibility as well as to interindividual variability in response to chemotherapy. On the other hand, hypermorphic polymorphisms were associated with Parkinson's and Alzheimer's disease. The I and D promoter variants and other NQO2 polymorphisms may impact cognitive decline, alcoholism and toxicity of several nervous system drugs. Future studies are required to fill several gaps in NQO2 research.

Decreased Expression of PLD2 Promotes EMT in Colorectal Cancer Invasion and Metastasis.

Background and Objectives: PLD2 has been identified as playing a critical role in cancer cell motility and migration and other pathophysiological processes. We investigated the expression of PLD2 and its biological functions and clinical implications in human colorectal cancer. Materials and Methods: In this study, the expressions of PLD2 were analyzed in CRC cell lines and CRC samples by RT-PCR, western blot and immunohistochemistry. The PLD enzyme activity was studied using an PLD detection kit. We also performed matrigel invasion assay to evaluate the invasive capabilities in CRC cells. The expressions of EMT-related markers were quantified at mRNA and protein level using RT-PCR and western blot. We performed high-throughput RNA sequencing on PLD2 knockdown and overexpression CRC cell lines to explore the changes in gene expression associated with PLD2. Result: Herein, we showed that PLD2 expression was relatively low in CRC cell lines and CRC samples and PLD2 deficiency was significantly correlated with more advanced clinical phenotype regarding lymphatic and distant metastasis and poor patient survival. We also detected that PLD2 knockdown favored epithelial-mesenchymal transition (EMT) and thus promoted CRC invasion and metastasis. Further exploration uncovered that the expressions of several important genes closely related to metabolic pathways in CRC were noticeably altered due to PLD2 deficiency, including ID1, IFIT4, OASL, IFIT2 and CTAG2. Conclusion: Our results revealed that PLD2 deficiency promotes cell invasion and metastasis in CRC via EMT indicating PLD2 might have an important implication in carcinogenesis and progression and would be a new therapeutic target for cancer treatment.

World Trade Center Exposure, DNA Methylation Changes, and Cancer: A Review of Current Evidence.

Introduction: Known carcinogens in the dust and fumes from the destruction of the World Trade Center (WTC) towers on 9 November 2001 included metals, asbestos, and organic pollutants, which have been shown to modify epigenetic status. Epigenome-wide association analyses (EWAS) using uniform (Illumina) methodology have identified novel epigenetic profiles of WTC exposure. Methods: We reviewed all published data, comparing differentially methylated gene profiles identified in the prior EWAS studies of WTC exposure. This included DNA methylation changes in blood-derived DNA from cases of cancer-free "Survivors" and those with breast cancer, as well as tissue-derived DNA from "Responders" with prostate cancer. Emerging molecular pathways related to the observed DNA methylation changes in WTC-exposed groups were explored and summarized. Results: WTC dust exposure appears to be associated with DNA methylation changes across the genome. Notably, WTC dust exposure appears to be associated with increased global DNA methylation; direct dysregulation of cancer genes and pathways, including inflammation and immune system dysregulation; and endocrine system disruption, as well as disruption of cholesterol homeostasis and lipid metabolism. Conclusion: WTC dust exposure appears to be associated with biologically meaningful DNA methylation changes, with implications for carcinogenesis and development of other chronic diseases.

GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma.

Simple SummaryThe development of uveal melanoma is a multifactorial and multi-step process, in which specific and recurrent mutations arise early. Among the recurrently mutated genes, GNAQ and GNA11 are involved in the process of carcinogenesis and are mutated in 80–90% of these tumours. Historically, there has been speculation as to whether these two genes are involved in the progression of primary uveal melanoma to metastatic disease, in addition to the oncogenic process itself. For this reason, both genes have been the subject of multiple research studies. Additionally, due to their high mutation rate in uveal melanoma, these genes and the downstream signaling pathways in which they are involved have been postulated as interesting therapeutic targets. This review aims to provide a current comprehensive view of what we know about GNAQ and GNA11 genes on oncogenesis, prognosis and therapeutic opportunities in uveal melanoma.The GNAQ and GNA11 genes are mutated in almost 80–90% of uveal melanomas in a mutually exclusive pattern. These genes encode the alpha subunits of the heterotrimeric G proteins, Gq and G11; thus, mutations of these genes result in the activation of several important signaling pathways, including phospholipase C, and activation of the transcription factor YAP. It is well known that both of them act as driver genes in the oncogenic process and it has been assumed that they do not play a role in the prognosis of these tumours. However, it has been hypothesised that mutations in these genes could give rise to molecularly and clinically distinct types of uveal melanomas. It has also been questioned whether the type and location of mutation in the GNAQ and GNA11 genes may affect the progression of these tumours. All of these questions, except for their implications in carcinogenesis, remain controversial. Uveal melanoma has a distinctive genetic profile, and specific recurrent mutations, which make it a potential candidate for treatment with targeted therapy. Given that the most frequent mutations are those observed in the GNAQ and GNA11 genes, and that both genes are involved in oncogenesis, these molecules, as well as the downstream signalling pathways in which they are involved, have been proposed as promising potential therapeutic targets. Therefore, in this review, special attention is paid to the current data related to the possible prognostic implications of both genes from different perspectives, as well as the therapeutic options targeting them.

Abstract 2250: Eosinophil-to-lymphocyte ratio and cancer risk in the UK Biobank

Abstract Background: Eosinophils exhibit anti-tumor cytotoxic responses in the tumor microenvironment. Some atopic diseases, characterized by elevated peripheral eosinophils, are inversely associated with cancer risk. The balance of atopy and immunity may be estimated by an eosinophil-to-lymphocyte ratio (ELR). This study aims to understand the role of ELR as a biomarker in carcinogenesis. Methods: We evaluated 445,404 adults aged 37-73 years at baseline in a prospective cohort study, the UK Biobank, who were cancer-free at initial assessment, had more than one year of follow-up, and had baseline white blood cell (WBC) count and differential measurements. ELR was categorized into quartiles. Incident cancers were ascertained from cancer registries from 2006-2015. Multivariable Cox regression was used to estimate per quartile ELR hazard ratios (aHRs) separately for 52 cancer sites, adjusted for age (quartiles), sex, race (white, non-white), smoking/alcohol (never, past, current), body mass index (<25, 25-30, ≥30 kg/m2) and total WBC (quartiles). Multiple comparisons were considered by a Bonferroni-corrected threshold (p<0.00096). Results: Over a median follow-up time of 6.9 years from baseline, 22,853 incident cancers were diagnosed. The median ELR was 0.07 (interquartile range=0.05-0.12). Higher ELR was inversely associated with overall cancer risk (aHR 0.98, 95%CI: 0.97-0.99; p-trend=0.0001) and chronic lymphocytic leukemia (0.50, 0.44-0.56; <0.0001). We also observed suggestive inverse ELR associations with other lymphocytic leukemia, acute and other myeloid leukemia, myeloma, melanoma and cancers of the nose/middle ear, tongue, prostate (aHR range: 0.63-0.97; p-trend<0.05). Per quartile increase of ELR was suggestively associated with increased risk of diffuse large B-cell lymphoma (aHR 1.13, 95%CI: 1.03-1.25; p-trend=0.01). Conclusion: We observed inverse associations between ELR and cancer risk in a large general population. Our findings suggest that atopy may be protective against cancer. Future research is warranted to elucidate the relationship between atopy and immunity in tumor surveillance. Impact/Significance: ELR presents a cost-effective and routinely accessible biomarker that may have implications for carcinogenesis, and may be leveraged to inform early detection of certain cancers. Citation Format: Jeanny Wang, Eric Engels, Minkyo Song. Eosinophil-to-lymphocyte ratio and cancer risk in the UK Biobank [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 2250.

Human Papillomavirus Modulates Matrix Metalloproteinases During Carcinogenesis: Clinical Significance and Role of Viral Oncoproteins.

Human papillomavirus (HPV) infections are associated with cervical cancer and other anogenital cancers. Despite progresses in HPV vaccination and screening, these cancers still show high incidence and mortality, requiring improved prognostic markers and tailored therapies. This review addresses the role of Matrix metalloproteinases (MMPs) in HPV-induced cancers and the modulation of MMP expression by HPV oncoproteins. Scientific literature indexed in PubMed and ScienceDirect about Human papillomavirus modulates matrix metalloproteinases was retrieved and critically analyzed, to obtain an overview of expression patterns and their implications for carcinogenesis and patient prognosis. Matrix metalloproteinases such as MMP1, MMP9 and MMP13 have been associated with patient prognosis in HPV-induced cancers and play a major role in the degradation of the extracellular matrix, tumor invasion and metastasis. The HPV E2 and E7 oncoproteins regulate MMP expression via AKT, MEK/ERK and AP-1 signaling among other mechanisms. Increased expression of MMPs is associated with cancer progression and poor prognosis in multiple HPV-induced cancers, suggesting their potential use as prognostic markers. The identification of specific signaling pathways that mediate MMP regulation by HPV is essential for developing efficient new cancer therapies.

Mst2 Overexpression Inhibits Thyroid Carcinoma Growth and Metastasis by Disrupting Mitochondrial Fitness and Endoplasmic Reticulum Homeostasis.

Although the incidence of thyroid carcinoma has increased over the past several decades, it has an excellent prognosis and overall 5-year survival, with a stable mortality rate, except in cases with advanced stages or rare malignant tumor types. Biomarkers have emerged as effective targets of molecular therapy against thyroid carcinoma due to their rapid and convenient detection; however, there has been little clinical application. Macrophage stimulating 2 (Mst2) is a proapoptotic protein with implications in carcinogenesis and metastasis. We found that Mst2 overexpression-induced endoplasmic reticulum (ER) stress in MDA-T32 thyroid carcinoma cells, accompanied by elevated caspase-12 activity, increased apoptotic rate, and reduced cell viability. In addition, Mst2 overexpression contributed to mitochondrial damage, as evidenced by increased mitochondrial oxidative stress and activated the mitochondrial apoptotic pathway. Inhibition of the JNK pathway abolished these effects. These results show Mst2 to be a novel tumor suppressor that induces mitochondrial dysfunction and ER stress via the JNK pathway. Thus, Mst2 could potentially serve as a biomarker for developing targeted therapy against thyroid carcinoma.

Abstract 2663: Determining the role of altered redox metabolism in lung tumorigenesis

Abstract The purpose of this study is to determine the pathways by which short-term cigarette smoke exposure induces expression of the cystine-glutamate antiporter xCT (SLC7A11) and its downstream implications in carcinogenesis. BEAS-2B lung epithelial cells and their tumorigenic counterpart, B39-TL cells, were exposed to cigarette smoke condensate (CSC) for 3-15 days. Cells were also exposed to a range of inhibitors. Erastin and buthionine sulfoximine (BSO) are inhibitors of various steps in the glutathione synthesis pathway, found to be hyperactive in xCT-overexpressing cells. Cells were also exposed to the drug mito-2-hydroxybenzoic acid (mito-2-HOBA), which scavenges isolevuglandins, reactive γ-ketoaldehydes implicated in oxidative stress and carcinogenesis. Expression of xCT and related proteins was measured using Western blotting. Glutathione levels were detected using the luciferase-based GSH-Glo assay (Promega). Oxidative stress was detected using dihydroethidium (DHE) fluorescence. It was found that CSC exposure significantly increased the expression of xCT and SLC1A5, a transporter that potentially works in synergy with xCT, and that tumorigenic B39-TL cells had significantly increased xCT and SLC1A5 expression compared to BEAS-2B cells. In addition, BEAS-2B cells exposed to CSC and a glutathione synthesis inhibitor such as erastin or BSO showed faster depletion of glutathione than cells treated with only inhibitor. Finally, it was found that BEAS-2B cells treated for 3 days with CSC did not show increased levels of superoxide compared to control cells. However, cells treated with CSC and mito-2-HOBA together showed significantly increased superoxide. These data suggest that CSC induces an antioxidant response which is ablated by mito-2-HOBA. This antioxidant response seems to at least partially rely on glutathione synthesis fueled by xCT, as evidenced by inhibitor studies. The response also seems to be activated by isolevuglandins, because removing these molecules significantly raises oxidative stress. The mechanistic link between CSC exposure, isolevuglandin generation, and xCT/glutathione induction will be clarified in further experiments. Citation Format: Alex Camai. Determining the role of altered redox metabolism in lung tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2663.

Complex interaction of adipokines in breast cancer and anti-tumour immunity; a new paradigm for cancer treatment

Obesity and its related complications have been the pressing disease pandemic affecting the developed world. It is well-established that the direct consequence of obesity in the cardiovascular system resulting in many diseases. However, its implications in carcinogenesis, cancer treatment and one’s anti-tumour immunity are gradually unfolding. To understand how fat cells can affect these, one needs to explore how the fat cell affects epithelial and immune cells. To this end, we explore the way how the adipocytes, via its production of adipokines, influence these cells, resulting in early epithelial cell transformation into cancer cells and influencing anti-tumour immunity once the cancer is established. In order to simplify our discussion, we focus this review on breast cancer. We propose that to have an effective therapy for cancer treatment, we need to intervene at the adipokine interaction with epithelial cells, cancer cells, and immune cells. In this review we also decipher the potential therapeutic targets in controlling carcinogenesis and disease progression.

Genomics and molecular analysis of RPL9 and LIAS in lung cancer: Emerging implications in carcinogenesis

Abstract Worldwide, lung cancer is a leading cause of cancer-related deaths and is the most commonly diagnosed form of cancer. A major characteristic of lung cancer is its profound clinical, histological and molecular heterogeneity. This heterogeneity is not only spatial but also temporal thus stressing the need for personalized patient-tailored treatment planning. The current optimal treatment planning is currently based on real-time monitoring of the evolving molecular profiling of the tumour throughout the course of the disease and treatment. In the current work, we will investigate the emerging role that that RPL9 and LIAS could have in carcinogenesis. While the aberrant expression of RPL9 has already been shown to occur in colorectal cancer its role in lung cancer is not yet known. In a similar manner, the role of LIAS, as a metabolism-linked gene, in cancer biology and especially in lung cancer is still unknown. Emerging research reveals both RPL9 and LIAS as interacting partners and apoptosis resistance genes. The aim of this study is to determine the differential expression of the rpl9 and lias genes in both normal lung tissue and lung cancer samples. This was achieved by using in situ hybridization (ISH) and quantitative Real-time PCR (qPCR). Further data on the role played by RPL9 in lung cancer was established through the use of in silico bioinformatic analysis. This was done in order to map biological pathways enriched by the expression of these genes. Both the KEGG pathway and Reactome analysis confirmed the role of these genes in RNA metabolic pathways. Furthermore, RPL9 was shown to play a role in signal transduction, autophagy, and cellular response to stress pathways. The function of these two proteins overlapped with regard to protein metabolism. STRING analysis also demonstrated an interaction between RPL9 and LIAS. Here we propose that the aberrant expression of RPL9 and LIAS may contribute to lung carcinogenesis and can be targeted for molecular therapy.

Post-Translational Modifications of PCNA in Control of DNA Synthesis and DNA Damage Tolerance-the Implications in Carcinogenesis.

The faithful DNA replication is a critical event for cell survival and inheritance. However, exogenous or endogenous sources of damage challenge the accurate synthesis of DNA, which causes DNA lesions. The DNA lesions are obstacles for replication fork progression. However, the prolonged replication fork stalling leads to replication fork collapse, which may cause DNA double-strand breaks (DSB). In order to maintain genomic stability, eukaryotic cells evolve translesion synthesis (TLS) and template switching (TS) to resolve the replication stalling. Proliferating cell nuclear antigen (PCNA) trimer acts as a slide clamp and encircles DNA to orchestrate DNA synthesis and DNA damage tolerance (DDT). The post-translational modifications (PTMs) of PCNA regulate these functions to ensure the appropriate initiation and termination of replication and DDT. The aberrant regulation of PCNA PTMs will result in DSB, which causes mutagenesis and poor response to chemotherapy. Here, we review the roles of the PCNA PTMs in DNA duplication and DDT. We propose that clarifying the regulation of PCNA PTMs may provide insights into understanding the development of cancers.

Overexpressed sFRP3 exerts an inhibitory effect on hepatocellular carcinoma via inactivation of the Wnt/β-catenin signaling pathway.

Hepatocellular carcinoma (HCC) is recognized as the most common malignancy of the liver in adults. Many human cancers have been associated with the oncogenic activation of the Wnt/β-catenin signaling pathway. The secreted frizzled-related proteins (sFRPs) function as negative regulators of the Wnt signaling and have important implications in carcinogenesis. This study aims to investigate the possible regulatory effects of sFRP3 on the Wnt/β-catenin signaling pathway and their interactions in HCC occurrence. Firstly, sFRP3 expression was quantified in the collected cancer and adjacent normal tissue samples from HCC patients. The lowly expressed sFRP3 in HCC tissues was found to be correlated with HCC development. The expression of sFRP3 was regulated by a lentivirus-based packaging system, and the Wnt/β-catenin signaling pathway was inactivated by DDK-1 in HepG2 cells. The expressions of Wnt1, β-catenin and the nuclear translocation of β-catenin were determined, both of which were down-regulated by sFRP3 overexpression. CCK8 assay, EdU staining, Colony formation assay, flow cytometry, scratch test and Transwell assay were employed to test cell viability, proliferation, cell cycle, apoptosis, migration and invasion, respectively. Overexpressed levels of sFRP3 were found to produce a reduction in MMP-2, MMP-7, MMP-9, PCNA, Ki67, and Bcl-2 expressions but an increase in the expressions of caspase-3 and Bax. In addition, overexpression of sFRP3 inhibited cell proliferation, migration, invasion, and colony formation, but promoted cell cycle arrest and cell apoptosis in HCC cells. The addition of the Wnt/β-catenin signaling pathway inhibitor, DKK-1, reversed the contributory effect of sFRP3 silencing on HCC development. Lastly, in vivo tumor formation was inhibited by enforced sFRP3 expressions. The obtained results suggested that sFRP3 acts as an anti-oncogene in HCC by inhibiting the activation of the Wnt/β-catenin signaling pathway.

Progressing from Recurring Tissue Injury to Genomic Instability: A New Mechanism of Neutrophil Pathogenesis.

Aberrant neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis. While the genotoxic function of PMNs and its implications in carcinogenesis have been primarily associated with oxidative stress, recent work by Butin-Israeli and colleagues has defined a novel mechanism where PMN-derived microparticles through the delivery and activity of specific miRNAs promoted formation of double-strand breaks (DSBs), and in parallel, suppressed DSB repair through the downregulation of lamin B1 and Rad51. Respective downregulation of these two proteins compromised the nuclear envelope and high-fidelity repair by homologous recombination, increasing DSB accumulation and aneuploidy. This discovery defined a novel mode of action where PMN-mediated suppression of DSB repair leading to genomic instability in the injured mucosa may facilitate progression toward colorectal cancer.

A comprehensive overview of mitochondrial DNA 4977-bp deletion in cancer studies.

Mitochondria are cellular machines essential for energy production. The biogenesis of mitochondria is a highly complex and it depends on the coordination of the nuclear and mitochondrial genome. Mitochondrial DNA (mtDNA) mutations and deletions are suspected to be associated with carcinogenesis. The most described mtDNA deletion in various human cancers is called the 4977-bp common deletion (mDNA4977) and it has been explored since two decades. In spite of that, its implication in carcinogenesis still unknown and its predictive and prognostic impact remains controversial. This review article provides an overview of some of the cellular and molecular mechanisms underlying mDNA4977 formation and a detailed summary about mDNA4977 reported in various types of cancers. The current knowledges of mDNA4977 as a prognostic and predictive marker are also discussed.

Reactive Oxygen and Nitrogen Species-Induced Protein Modifications: Implication in Carcinogenesis and Anticancer Therapy.

Cancer is a complex disorder extremely dependent on its microenvironment and highly regulated by multiple intracellular and extracellular stimuli. Studies show that reactive oxygen and nitrogen species (RONS) play key roles in cancer initiation and progression. Accumulation of RONS caused by imbalance between RONS generation and activity of antioxidant system (AOS) has been observed in many cancer types. This leads to alterations in gene expression levels, signal transduction pathways, and protein quality control machinery, that is, processes that regulate cancer cell proliferation, migration, invasion, and apoptosis. This review focuses on the latest advancements evidencing that RONS-induced modifications of key redox-sensitive residues in regulatory proteins, that is, cysteine oxidation/S-sulfenylation/S-glutathionylation/S-nitrosylation and tyrosine nitration, represent important molecular mechanisms underlying carcinogenesis. The oxidative/nitrosative modifications cause alterations in activities of intracellular effectors of MAPK- and PI3K/Akt-mediated signaling pathways, transcription factors (Nrf2, AP-1, NFκB, STAT3, and p53), components of ubiquitin/proteasomal and autophagy/lysosomal protein degradation systems, molecular chaperones, and cytoskeletal proteins. Redox-sensitive proteins, RONS-generating enzymes, and AOS components can serve as targets for relevant anticancer drugs. Chemotherapeutic agents exert their action via RONS generation and induction of cancer cell apoptosis, while drug resistance associates with RONS-induced cancer cell survival; this is exploited in selective anticancer therapy strategies. Cancer Res; 78(21); 6040-7. ©2018 AACR.

Modeling hepatitis C virus protein and p53 interactions in hepatocytes: Implications for carcinogenesis

Hepatitis C virus (HCV) infection has reached epidemic proportions worldwide. Individuals with chronic HCV infection and without access to treatment are at high risk for developing hepatocellular carcinoma (HCC), a liver cancer that is rapidly fatal after diagnosis. A number of factors have been identified that contribute to HCV-driven carcinogenesis such as scarring of the liver, and chronic inflammation. Recent evidence indicates a direct role for HCV-encoded proteins themselves in oncogenesis of infected hepatocytes. The viral protein HCV core has been shown to interact directly with the host tumor suppressor protein p53, and to modulate p53-activity in a biphasic manner. Here, biochemically-motivated mathematical models of HCV-p53 interactions are developed to elucidate the mechanisms underlying this phenomenon. We show that by itself, direct interaction between HCV core and p53 is insufficient to recapitulate the experimental data. We postulate the existence of an additional factor, activated by HCV core that inhibits p53 function. We present experimental evidence in support of this hypothesis. The model including this additional factor reproduces the experimental results, validating our assumptions. Finally, we investigate what effect HCV core-p53 interactions could have on the capacity of an infected hepatocyte to repair damage to its DNA. Integrating our model with an existing model of the oscillatory response of p53 to DNA damage predicts a biphasic relationship between HCV core and the transformative potential of infected hepatocytes. In addition to providing mechanistic insights, these results suggest a potential biomarker that could help in identifying those HCV patients most at risk of progression to HCC.

Phospholipidation of nuclear proteins by the human papillomavirus E6 oncoprotein: implication in carcinogenesis.

Phospholipids regulate numerous cellular functions and their deregulation is known to be associated with cancer development. Here, we show for the first time that expression of the E6 oncoprotein of human papillomavirus type 8 (HPV8) leads to a profound increase in nuclear phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) lipid levels in monolayer cultures, that led to an aberrant phospholipidation of cellular proteins. Elevated PI(4,5)P2 levels in organotypic skin cultures, skin tumors of K14-HPV8-E6 transgenic mice as well as HPV8 positive skin carcinomas highly suggest a decisive role of PI(4,5)P2 in HPV associated squamous-cell-carcinoma development. Furthermore, mass-spectrometric analysis confirmed an increase of PI(4,5)P2, which was characterized by a shift in the distribution of lipid species. PI(4,5)P2 upregulation was independent of E6 interference with MAML1. However, E6 does interfere with the PI(4,5)P2 metabolic pathway by upregulation of phosphatidylinositol-4-phosphate-5-kinase type I and phosphatidylinositol-5-phosphate 4-kinase type II as well as the binding to 5’-phosphatase OCRL and phosphatidylinositol. All of these mechanisms combined may contribute to PI(4,5)P2 elevation in E6 positive cells. The identification of CAND1 and SND1 – two proteins known to be involved in carcinogenic processes – were significantly stronger phospholipidized in the presence of E6. In conclusion we provide evidence that the modulation of the PI(4,5)P2 metabolism is a novel oncogenic mechanism relevant for HPV-induced carcinogenesis.

Binding Affinity of 17-b-ethinylestradiol to Normal and Mutant Types of Estrogen Receptors An in silico evaluation

Estrogen receptors (ERs)are nuclear transcription factor receptorsthat play important roles in gene expression and cell cycle regulation. Because of their ligand-activated signaling implication in carcinogenesis,ERs are extensively researched as protein targets for anti-cancer drug discovery active in certain types of tumors. However, a major drawback is the emergence of wild type tumors withoverexpressed mutant variants of ER, which become resistant to estrogen inhibitor drugs. Herein we studied the binding mode and affinity of the semisynthetic estrogen agonist, 17-b-estradiol (E2) in normal and mutant variants of ERs, by means of molecular docking. Our results showed a small decrease in binding affinity, recorded in mutant variants of ERa and a change in the binding interactions formed when the compound wasdocked in an agonist-bound conformation of the ERa . Nevertheless we concluded that even if the binding affinity showed a small decrease in the case of mutant type receptors,E2 potency towards ER�won�t register a downward trend.