Stages Of Carcinogenesis Research Articles

Inhibition of PORCN Blocks Wnt Signaling to Attenuate Progression of Oral Carcinogenesis.

Oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, referred to as oral dysplasia. We recently reported that oral dysplasia is associated with aberrant activation of the Wnt/β-catenin pathway, due to overexpression of Wnt ligands in a Porcupine (PORCN)-dependent manner. Pharmacologic inhibition of PORCN precludes Wnt secretion and has been proposed as a potential therapeutic approach to treat established cancers. Nevertheless, there are no studies that explore the effects of PORCN inhibition at the different stages of oral carcinogenesis. We performed a model of tobacco-induced oral cancer in vitro, where dysplastic oral keratinocytes (DOK) were transformed into oral carcinoma cells (DOK-TC), and assessed the effects of inhibiting PORCN with the C59 inhibitor. Similarly, an in vivo model of oral carcinogenesis and ex vivo samples derived from patients diagnosed with oral dysplasia and OSCC were treated with C59. Both in vitro and ex vivo oral carcinogenesis approaches revealed decreased levels of nuclear β-catenin and Wnt3a, as observed by immunofluorescence and IHC analyses. Consistently, reduced protein and mRNA levels of survivin were observed after treatment with C59. Functionally, treatment with C59 in vitro resulted in diminished cell migration, viability, and invasion. Finally, by using an in vivo model of oral carcinogenesis, we found that treatment with C59 prevented the development of OSCC by reducing the size and number of oral tumor lesions. The inhibition of Wnt ligand secretion with C59 represents a feasible treatment to prevent the progression of early oral lesions toward OSCC.

The hepatocellular carcinoma (HCC) stage carcinogenesis is associated with genomic instability features

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, which accounts for over 80% of liver tumors. In the study, the current objective is investigating the entire mutational background of the HCC tumors in a single study because it is challenging to explore the many genomic disparities. The study collected DNA-dependent gene sets such as epigenetic modifications, DNA repair, DNA damage response, replication stress, and other related signatures from the molecular signatures database. It investigated their expression patterns in genome-wide expression profiles of liver cancer cohorts by Z score-based pathway activation scoring. Furthermore, these gene set features were validated with a pan-cancer atlas profile. Recurrence is the primary concern in tumors that have regeneration features. Hence, these effects are also further reconfirmed at the recurrence level. Based on activation pattern results, most genomic instabilities feature gene sets activated in the HCC stage tumors rather than other stages. Moreover, these genomic instabilities features are further concluded from that i) The signatures of epigenetic modifications, loss of DNA repair activity, dysregulation of DNA damage response, and replication stress are highly elevated in the HCC stage because of mutation and carcinogenic effects, ii) In addition, hyper DNA helicase activity, transcriptional dysregulation, telomere maintenance, and cell division-related gene sets are also highly enhanced due to proliferation and survival properties of the HCC tumors, and iii) This gene sets an activated in genomic instability comprising subtypes (chromosomal instability and microsatellite instability) of pan-cancer tumor cohort, and these results also reconfirm that these gene sets have genomic instability features. This instability and its dysregulation also have similar impacts at the level of recurrence HCC tumor carcinogenesis. Thus, the potential relevance of molecular signatures identified in terms of outcome prediction and research study in this direction would probably produce significant biological information that may aid in classifying the patients more accurately and providing suggestions for appropriate therapy.

Role of Dietary Phytochemicals in Targeting Human miRNAs for Cancer Prevention and Treatment.

MicroRNAs (miRNAs - ~22 nucleotides) are a type of non-coding RNAs that are involved in post-transcriptional gene silencing. They are known to regulate gene expression in diverse biological processes, such as apoptosis, development, and differentiation. Several studies have demonstrated that cancer initiation and progression are highly regulated by miRNA expression. The nutrients present in the diet may regulate the different stages of carcinogenesis. Interestingly, plant-based foods, like fruits and vegetables, have been shown to play a significant role in cancer prevention. Phytochemicals are bioactive compounds derived from plant sources, and they have been shown to have antiinflammatory, antioxidant, and anticancer properties. Recent findings suggest that dietary phytochemicals, such as genistein, resveratrol, and curcumin, exert significant anticancer effects by regulating various miRNAs. In this review, we focus on the role of dietary phytochemicals in cancer prevention and treatment through the modulation of miRNA expression.

Gut virome profiling identifies an association between temperate phages and colorectal cancer promoted by Helicobacter pylori infection

ABSTRACT Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. While a close correlation between chronic Helicobacter pylori infection and CRC has been reported, the role of the virome has been overlooked. Here, we infected Apc-mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive metagenomics analysis of H. pylori-induced changes in lower gastrointestinal tract bacterial and viral communities. We observed an expansion of temperate phages in H. pylori infected Apc +/1638N mice at the early stage of carcinogenesis. Some of the temperate phages were predicted to infect bacteria associated with CRC, including Enterococcus faecalis. We also observed a high prevalence of virulent genes, such as flgJ, cwlJ, and sleB, encoded by temperate phages. In addition, we identified phages associated with pre-onset and onset of H. pylori-promoted carcinogenesis. Through co-occurrence network analysis, we found strong associations between the viral and bacterial communities in infected mice before the onset of carcinogenesis. These findings suggest that the expansion of temperate phages, possibly caused by prophage induction triggered by H. pylori infection, may have contributed to the development of CRC in mice by interacting with the bacterial community.

Spermidine Suppresses Oral Carcinogenesis through Autophagy Induction, DNA Damage Repair, and Oxidative Stress Reduction

Autophagy has been proposed to play a dual role in cancer-as a tumor suppressor in early stages and oncogenicin late stages of tumorigenesis. This study investigated the role of autophagy in oral carcinogenesis using the model of oral squamous cell carcinoma (OSCC) induced by carcinogen 4-nitroquinoline 1-oxide (4NQO), mimicking molecular and histopathologic aspects of human OSCC. The induction of autophagy by spermidine (SPD) treatment reduced the severity of lesions and the incidence of OSCC in mice exposed to 4NQO. On the other hand, autophagy inhibition by chloroquine treatment had no protection. The comet assay indicated that SPD reduced 4NQO-induced DNA damage, likely related to the activation of DNA repair and the decrease of reactive oxygen species. As sphingolipid alterations have been reported in OSCC, sphingolipids in the tongue and plasma of animals were analyzed and plasma C16 ceramide levels were shown to increase proportionally to lesion severity, indicating its potential as a biomarker. Mice exposed to 4NQO plus SPD had lower levels of C16 ceramide than the 4NQO group, which indicated SPD's ability to prevent the 4NQO-induced carcinogenesis. Together, these data indicate that activation of autophagy has a tumor suppressor role during the early stages of oral carcinogenesis. Because of its ability to induce autophagy accompanied by reduced oxidative stress and DNA damage, SPD may have a protective action against chemically induced oral cancer.

Changing epidemiology of colorectal cancer - birth cohort effects and emerging risk factors.

Incidence and mortality of colorectal cancer (CRC) are increasing worldwide, suggesting broad changes in the epidemiology of CRC. In this Review, we discuss the changes that are becoming evident, including trends in CRC incidence and mortality by age and birth cohort, and consider the contributions of early-life exposures and emerging risk factors to these changes. Importantly, incidence of CRC has increased among people born since the early 1950s in nearly all regions of the world. These so-called birth cohort effects imply the involvement of factors that influence the earliest stages of carcinogenesis and have effects across the life course. Accumulating evidence supports the idea that early-life exposures are important risk factors for CRC, including exposures during fetal development, childhood, adolescence and young adulthood. Environmental chemicals could also have a role because the introduction of many in the 1950s and 1960s coincides with increasing incidence of CRC among people born during those years. To reverse the expected increases in the global burden of CRC, participation in average-risk screening programmes needs to be increased by scaling up and implementing evidence-based screening strategies, and emerging risk factors responsible for these increases need to be identified.

Curcumin and melphalan cotreatment induces cell cycle arrest and apoptosis in MDA-MB-231 breast cancer cells.

Breast cancer is the second most common type of cancer worldwide and the leading cause of cancer death in women. Dietary bioactive compounds may act at different stages of carcinogenesis, including tumor initiation, promotion, and progression. Spices have been used for thousands of years and have many bioactive compounds with chemopreventive and chemotherapeutic properties. Curcumin has a multitude of beneficial biological properties, including anti-inflammatory and anticancer effects. This study investigated the effects of cotreatment with curcumin and the chemotherapeutic drug melphalan in cultured MDA-MB-231 breast cancer cells. When used alone, both curcumin and melphalan had a cytotoxic effect on breast cancer cells. Combined treatment with 11.65µM of curcumin and 93.95µM of melphalan (CURC/MEL) reduced cell viability by 28.64% and 72.43% after 24h and 48h, respectively. CURC/MEL reduced the number of colony-forming units and increased ROS levels by 1.36-fold. CURC/MEL alter cell cycle progression, induce apoptosis, and upregulate caspases-3, -7, and -9, in MDA-MB-231 cells. Cotreatment with curcumin and melphalan have anti-breast cancer cells effects and represent a promising candidate for clinical testing.

Α Humanized RANKL Transgenic Mouse Model of Progestin-Induced Mammary Carcinogenesis for Evaluation of Novel Therapeutics.

Receptor activator of nuclear factor-κB ligand (RANKL) is critically involved in mammary gland pathophysiology, while its pharmaceutical inhibition is being currently investigated in breast cancer. Herein, we investigated whether the overexpression of human RANKL in transgenic mice affects hormone-induced mammary carcinogenesis, and evaluated the efficacy of anti-RANKL treatments, such as OPG-Fc targeting both human and mouse RANKL or Denosumab against human RANKL. We established novel MPA/DMBA-driven mammary carcinogenesis models in TgRANKL mice that express both human and mouse RANKL, as well as in humanized humTgRANKL mice expressing only human RANKL, and compared them to MPA/DMBA-treated wild-type (WT) mice. Our results show that TgRANKL and WT mice have similar levels of susceptibility to mammary carcinogenesis, while OPG-Fc treatment restored mammary ductal density, and prevented ductal branching and the formation of neoplastic foci in both genotypes. humTgRANKL mice also developed MPA/DMBA-induced tumors with similar incidence and burden to those of WT and TgRANKL mice. The prophylactic treatment of humTgRANKL mice with Denosumab significantly prevented the rate of appearance of mammary tumors from 86.7% to 15.4% and the early stages of carcinogenesis, whereas therapeutic treatment did not lead to any significant attenuation of tumor incidence or tumor burden compared to control mice, suggesting the importance of RANKL primarily in the initial stages of tumorigenesis. Overall, we provide unique genetic tools for investigating the involvement of RANKL in breast carcinogenesis, and allow the preclinical evaluation of novel therapeutics that target hormone-related breast cancers.

2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone from Cleistocalyx nervosum var. paniala seeds attenuated the early stage of diethylnitrosamine and 1,2-dimethylhydrazine-induced colorectal carcinogenesis

BackgroundDichloromethane extract of Cleistocalyx nervosum var. paniala seeds exhibited an anticarcinogenicity against chemically-induced the early stages of carcinogenesis in rats. This study aimed to identify anticarcinogenic compounds from C. nervosum seed extract (CSE). MethodsSalmonella mutation assay was performed to determine mutagenicity and antimutagenicity of partially purified and purified compounds of CSE. The anticarcinogenic enzyme-inducing activity was measured in Hepa1c1c7. Moreover, the anticancer potency was examined on various human cancer cell lines. The anticarcinogenicity of DMC was investigated using dual-organ carcinogenicity model. The number of preneoplastic lesions was evaluated in the liver and colon. The inhibitory mechanisms of DMC on liver- and colorectal carcinogenesis were investigated. ResultsSix partially purified fractions (MK1 – MK6) and purified compounds, including 2,4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) and hariganetin, were obtained from CSE. Among these fractions, MK4 and DMC presented the greatest antimutagenicity against indirect mutagens in bacterial model. Moreover, MK5 possessed an effective anticarcinogenic enzyme inducer in Hepa1c1c7. The MK4, DMC and CSE showed greater anticancer activity on all cell lines and exhibited the most effective toxicity on colon cancer cells. Furthermore, DMC inhibited the formation of colonic preneoplastic lesions in carcinogens-treated rats. It reduced PCNA-positive cells and frequency of BCAC in rat colon. DMC also enhanced the detoxifying enzyme, GST, in rat livers. ConclusionsDMC obtained from CSE may be a promising cancer chemopreventive compound of colorectal cancer process in rats. It could increase detoxifying enzymes and suppress the cell proliferation process resulting in prevention of post-initiation stage of colorectal carcinogenesis.

Let-7a Downregulation Accompanied by KRAS Mutation Is Predictive of Lung Cancer Onset in Cigarette Smoke-Exposed Mice.

Let-7 is a tumor suppressor microRNA targeting the KRAS lung oncogene. Let-7a downregulation is reversible during the early stages of lung carcinogenesis but is irreversible in cancer cells. The aim of this study is to shed light on the relationship between oncogene (KRAS) mutation and let-7a downregulation in cigarette smoke (CS)-induced lung carcinogenesis. A total of 184 strain H Swiss albino mice were either unexposed (control) or exposed to CS for 2 weeks (short CS) or 8 months (long CS). After 8 months, the lungs were individually collected. The following end points have been evaluated: (a) DNA methylation of the let-7a gene promoter by bisulphite-PCR and pyrosequencing; (b) let-7a expression by qPCR; (c) KRAS mutation by DNA pyrosequencing; (d) cancer incidence by histopathological examination. let-7a expression decreased by 8.3% in the mice exposed to CS for two weeks (CS short) and by 33.4% (p ≤ 0.01) in the mice exposed to CS for 8 months (CS long). No significant difference was detected in the rate of let-7a-promoter methylation between the Sham-exposed mice (55.1%) and the CS short-(53%) or CS long (51%)-exposed mice. The percentage of G/T transversions in KRAS codons 12 and 13 increased from 2.3% (Sham) to 6.4% in CS short- and to 11.5% in CS long-exposed mice. Cancer incidence increased significantly in the CS long-exposed mice (11%) as compared to both the Sham (4%) and the CS short-exposed (2%) mice. In the CS long-exposed mice, the correlation between let-7a expression and the number of KRAS mutations was positive (R = +0.5506) in the cancer-free mice and negative (R = -0.5568) in the cancer-bearing mice. The effects of CS-induced mutations in KRAS are neutralized by the high expression of let-7a in cancer-free mice (positive correlation) but not in cancer-bearing mice where an irreversible let-7a downregulation occurs (negative correlation). This result provides evidence that both genetic (high load of KRAS mutation) and epigenetic alterations (let-7a irreversible downregulation) are required to produce lung cancer in CS-exposed organisms.

Dietary phytochemicals targeting Nf-<i>K</i>B signalling pathways: Potential cancer chemoprevention strategy

Chemoprevention is an approach involving the use of natural or synthetic substances to prevent the risk of development many diseases including cancer. Nuclear factor–kappa B (NF-kB) signaling pathways is crucial in either inducing processes of inflammation and apoptosis. As a result, it is implicated in numerous stages of carcinogenesis through collaboration with several signaling pathways and molecules. This transcription factor may be regarded as key target for cancer chemoprevention. Phytochemicals available in food as well as green plants have been demonstrated to have cancer protection activities by modulating important cellular signaling pathways including NF-kB pathway. Numerous phytochemicals, primarily components of edible vegetables and plants, have been reported in the literature to modulate NF-kB. Suppressing NF-kB may provide protection to the normal cells against development and spread of cancer. Majority of phytochemicals use various mechanisms to inhibit NF-kB. Different phytochemicals combinations present in a natural food may enhance their modulating potential on NF-kB and consequently elicit cancer prevention. This article reviews the current understanding of the potential effect of some phytochemicals and their combinations on NF-kB activities.

A Review on some dietary phytochemicals as potential cancer chemoprevention and chemotherapeutic agents

Cancer is a disease with multiple etiologies and has gained the interest of researchers in search for its prevention and therapeutic targets. Mammalian cells are constantly exposed to electrophilic/oxidative stresses that are considered to be part of the most essential and pervasive causes of cancer. The Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial in either inducing or suppressing angiogenesis. As a result, it has been implicated in numerous stages of carcinogenesis through association with several signaling pathways and molecules. This transcription factor may be regarded as key target for chemoprevention of cancer. As a transcription factor, Nrf2 exert a great function in ARE-driven genes expression. More so, it plays an important role in the up-regulation of these genes towards oxidative challenges. Numerous phytochemicals especially in fruits as well as edible vegetables have shown to activate Nrf2 and elicit antioxidant response. Inducing the synthesis of antioxidant/phase II detoxifying enzymes (UDP-glucuronyltransferase, Heme oxygenase-1, NAD(P)H: quinone oxidoreductase and Glutathione-s-transferase) by natural compounds present in diet is among the most efficient approaches for cancer prevention in human. This review discusses Keap1-Nrf2-ARE pathway as a prime target for cancer chemoprevention, its underlying mechanisms and modulation by dietary phytochemicals as well as effects of combination of phytochemicals.

Thiosulfinates: Cytotoxic and Antitumor Activity.

Pharmacological value of some natural compounds makes them attractive for use in oncology. The sulfur-containing thiosulfinates found in plants of the genus Allium have long been known as compounds with various therapeutic properties, including antitumor. Over the last few years, the effect of thiosulfinates on various stages of carcinogenesis has been actively investigated. In vitro and in vivo studies have shown that thiosulfinates inhibit proliferation of cancer cells, as well as they induce apoptosis. The purpose of this review is to summarize current data on the use of natural and synthetic thiosulfinates in cancer therapy. Antitumor mechanisms and molecular targets of these promising compounds are discussed. A significant part of the review is devoted to consideration of a new strategy for treatment of oncological diseases - use of the directed enzyme prodrug therapy approach aiming to obtain antitumor thiosulfinates in situ.

Pellino 3 promotes the colitis-associated colorectal cancer through suppression of IRF4-mediated negative regulation of TLR4 signalling.

The incidence of colitis-associated colorectal cancer (CAC) has increased due to a high-nutrient diet, increased environmental stimuli and inherited gene mutations. To adequately treat CAC, drugs should be developed by identifying novel therapeutic targets. E3 ubiquitin-protein ligase pellino homolog 3 (pellino 3; Peli3) is a RING-type E3 ubiquitin ligase involved in inflammatory signalling; however, its role in the development and progression of CAC has not been elucidated. In this study, we studied Peli3-deficient mice in an azoxymethane/dextran sulphate sodium-induced CAC model. We observed that Peli3 promotes colorectal carcinogenesis with increased tumour burden and oncogenic signalling pathways. Ablation of Peli3 reduced inflammatory signalling activation at the early stage of carcinogenesis. Mechanistic studies indicate that Peli3 enhances toll-like receptor 4 (TLR4)-mediated inflammation through ubiquitination-dependent degradation of interferon regulatory factor 4, a negative regulator of TLR4 in macrophages. Our study suggests an important molecular link between Peli3 and colonic inflammation-mediated carcinogenesis. Furthermore, Peli3 can be a therapeutic target in the prevention and treatment of CAC.

BACCHARIN FROM GREEN PROPOLIS: A REVIEW OF ITS ANTIPROLIFERATIVE EFFECTS

Baccharin (3-prenyl-4-dihydrocinnamoyloxy-cinnamic acid) is a prenylated phenolic compound found in the extract of the Baccharis dracunculifolia plant, as well as in green propolis. It is one of the main components of this resinous material, which results from the interaction between bees and plants. This substance has been extensively studied for its biological effects, mainly its anti-inflammatory and antitumor activities. In this literature review, we have compiled several articles available between 1999 and 2022 that discuss scientific research carried out on baccharin. The objective is to explore the already evaluated beneficial effects of this compound in different types of tumors. The cancer begins with a genetic mutation that transforms a normal cell into a mutated cell. Subsequently, important mechanisms for its development and progression occur, including increased proliferation, evasion of apoptosis, angiogenesis, invasion, and metastasis. In this regard, numerous studies are being conducted to identify natural compounds that can act on these stages of carcinogenesis, including the components of green propolis. It has already been demonstrated that baccharin can act at different stages of tumor development, exhibiting antimitotic, antiangiogenic, pro-apoptotic, and immunomodulatory activities. Additionally, baccharin has been found to interfere with carcinogenic metabolic pathways and exhibit genotoxic effects. Baccharin has demonstrated a significant antitumor activity when applied to melanoma cells, colon cancer, gastric cancer, hepatocarcinoma, sarcoma, prostate cancer, breast cancer, and leukemia tumor cells. Therefore, the studies cited in this review provide evidence of baccharin's ability to inhibit relevant steps in the carcinogenic process of different types of tumors.

Association of Antibody Responses to Fusobacterium nucleatum and Streptococcus gallolyticus Proteins with Colorectal Adenoma and Colorectal Cancer

BackgroundStreptococcus gallolyticus subspecies gallolyticus (SGG) and Fusobacterium (F.) nucleatum have been implicated in colorectal carcinogenesis. Here, the association of immune responses to bacterial exposure with advancing stages of colorectal neoplasia was assessed by multiplex serology.MethodsImmunoglobulin (Ig) A and G antibody responses to eleven proteins each of F. nucleatum and SGG were measured in plasma of controls (n = 100) and patients with colorectal cancer (CRC, n = 25), advanced adenoma (n = 82), or small polyps (n = 85). Multivariable logistic regression was used to evaluate the association of bacterial sero-positivity with colorectal neoplasia. In a cohort subset with matched data (n = 45), F. nucleatum sero-positivity was correlated with bacterial abundance in both neoplastic and matched normal tissue.ResultsIgG sero-positivity to Fn1426 of F. nucleatum was associated with an increased CRC risk (OR = 4.84; 95% CI 1.46–16.0), while IgA sero-positivity to any SGG protein or specifically Gallo0272 and Gallo1675 alone was associated with increased advanced adenoma occurrence (OR = 2.02, 95% CI 1.10–3.71; OR = 2.67, 95% CI 1.10–6.46; and OR = 6.17, 95% CI 1.61–23.5, respectively). Only F. nucleatum abundance in the normal mucosa positively correlated with the IgA response to the Fn1426 antigen (Correlation coefficient (r) = 0.38, p < 0.01).ConclusionAntibody responses to SGG and F. nucleatum were associated with occurrence of colorectal adenomas and CRC, respectively. Further studies are needed to clarify the role these microbes or the immune response to their antigens may have in colorectal carcinogenesis stages.Graphical

Cyclooxygenase Inhibitors and Cancer: The Missing Pieces.

At 125, aspirin still represents the cornerstone of anti-platelet therapy for the acute treatment and long-term prevention of atherothrombosis. The development of a selective regimen of low-dose aspirin for the inhibition of platelet thromboxane production was key to maximizing its antithrombotic efficacy and minimizing its gastrointestinal toxicity. Based on about 50 observational studies, published over the past 30 years, aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The apparent chemopreventive effect of aspirin has been confirmed in post-hoc analyses of randomized cardiovascular trials and their meta-analyses. Moreover, prevention of sporadic colorectal adenoma recurrence was demonstrated by randomized controlled trials of low-dose aspirin and selective cyclooxygenase-2 inhibitors. A single placebo-controlled randomized trial of aspirin has shown long-term colorectal cancer prevention in patients with the Lynch syndrome. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the existing evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle. SIGNIFICANCE STATEMENT: Low-dose aspirin and other cyclooxygenase inhibitors have been associated with a reduced risk of colorectal cancer, and possibly other digestive tract cancers. The sequential involvement of thromboxane-dependent platelet activation and cyclooxygenase-2-driven inflammatory response in the early stages of colorectal carcinogenesis may explain these clinical benefits. The aim of this mini-review is to analyze the evidence for a chemopreventive effect of aspirin and other cyclooxygenase inhibitors and discuss the missing pieces of this mechanistic and clinical puzzle.

P-70 Co-infection with Helicobacter pylori and Epstein-Barr virus occurs at early stage of gastric carcinogenesis

P-70 Co-infection with Helicobacter pylori and Epstein-Barr virus occurs at early stage of gastric carcinogenesis

The scientific basis for the use of the linear no-threshold (LNT) model at low doses and dose rates in radiological protection

The linear no-threshold (LNT) model was introduced into the radiological protection system about 60 years ago, but this model and its use in radiation protection are still debated today. This article presents an overview of results on effects of exposure to low linear-energy-transfer radiation in radiobiology and epidemiology accumulated over the last decade and discusses their impact on the use of the LNT model in the assessment of radiation-related cancer risks at low doses. The knowledge acquired over the past 10 years, both in radiobiology and epidemiology, has reinforced scientific knowledge about cancer risks at low doses. In radiobiology, although certain mechanisms do not support linearity, the early stages of carcinogenesis comprised of mutational events, which are assumed to play a key role in carcinogenesis, show linear responses to doses from as low as 10 mGy. The impact of non-mutational mechanisms on the risk of radiation-related cancer at low doses is currently difficult to assess. In epidemiology, the results show excess cancer risks at dose levels of 100 mGy or less. While some recent results indicate non-linear dose relationships for some cancers, overall, the LNT model does not substantially overestimate the risks at low doses. Recent results, in radiobiology or in epidemiology, suggest that a dose threshold, if any, could not be greater than a few tens of mGy. The scientific knowledge currently available does not contradict the use of the LNT model for the assessment of radiation-related cancer risks within the radiological protection system, and no other dose-risk relationship seems more appropriate for radiological protection purposes.

Genome-wide DNA methylation profiling of HPV-negative leukoplakia and gingivobuccal complex cancers

BackgroundGingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis.ResultsThere is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls.ConclusionsOur findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC.Graphical abstract