Development of Epstein-Barr virus-associated gastric cancer:Infection,inflammation,and oncogenesis

Epstein-Barr virus(EBV)-associated gastric cancer(EBVaGC)cells originate from a single-cell clone infected with EBV.However,more than 95%of patients with gastric cancer have a history of Helicobacter pylori(H.pylori)infection,and H.pylori is a major causative agent of gastric cancer.Therefore,it has long been argued that H.pylori infection may affect the development of EBVaGC,a subtype of gastric cancer.Atrophic gastrointestinal inflammation,a symptom of H.pylori infection,is observed in the gastric mucosa of EBVaGC.Therefore,it remains unclear whether H.pylori infection is a cofactor for gastric carcinogenesis caused by EBV infection or whether H.pylori and EBV infections act independently on gastric cancer formation.It has been reported that EBV infection assists in the oncogenesis of gastric cancer caused by H.pylori infection.In contrast,several studies have reported that H.pylori infection accelerates tumorigenesis initiated by EBV infection.By reviewing both clinical epidemiological and experimental data,we reorganized the role of H.pylori and EBV infections in gastric cancer formation.

Histo-molecular oncogenesis of pancreatic cancer:From precancerous lesions to invasive ductal adenocarcinoma

Pancreatic cancer is a lethal malignancy,whose precursor lesions are pancreatic intraepithelial neoplasm,intraductal papillary mucinous neoplasm,intraductal tubulopapillary neoplasm,and mucinous cystic neoplasm.To better understand the biology of pancreatic cancer,it is fundamental to know its precursors and to study the mechanisms of carcinogenesis.Each of these precursors displays peculiar histological features,as well as specific molecular alterations.Starting from such pre-invasive lesions,this review aims at summarizing the most important aspects of carcinogenesis of pancreatic cancer,with a specific focus on the recent advances and the future perspectives of the research on this lethal tumor type.

Human papillomavirus and gastrointestinal cancer: A review

Human papillomavirus(HPV) is one of the most common sexually transmitted infections worldwide. Exposure to HPV is very common,and an estimated 65%-100% of sexually active adults are exposed to HPV in their lifetime. The majority of HPV infections are asymptomatic,but there is a 10% chance that individuals will develop a persistent infection and have an increased risk of developing a carcinoma. The International Agency for Research on Cancer has found that the following cancer sites have a strong causal relationship with HPV: cervix uteri,penis,vulva,vagina,anus and oropharynx,including the base of the tongue and the tonsils. However,studies of the aetiological role of HPV in colorectal and esophageal malignancies have conflicting results. The aim of this review was to organize recent evidence and issues about the association between HPV infection and gastrointestinal tumours with a focus on esophageal,colorectal and anal cancers. The ultimate goal was to highlight possible implications for prognosis and prevention.

Helicobacter pylori,gastric microbiota and gastric cancer relationship:Unrolling the tangle

Helicobacter pylori infection(Hp-I)represents a typical microbial agent intervening in the complex mechanisms of gastric homeostasis by disturbing the balance between the host gastric microbiota and mucosa-related factors,leading to inflammatory changes,dysbiosis and eventually gastric cancer.The normal gastric microbiota shows diversity,with Proteobacteria[Helicobacter pylori(H.pylori)belongs to this family],Firmicutes,Actinobacteria,Bacteroides and Fusobacteria being the most abundant phyla.Most studies indicate that H.pylori has inhibitory effects on the colonization of other bacteria,harboring a lower diversity of them in the stomach.When comparing the healthy with the diseased stomach,there is a change in the composition of the gastric microbiome with increasing abundance of H.pylori(where present)in the gastritis stage,while as the gastric carcinogenesis cascade progresses to gastric cancer,the oral and intestinal-type pathogenic microbial strains predominate.Hp-I creates a premalignant environment of atrophy and intestinal metaplasia and the subsequent alteration in gastric microbiota seems to play a crucial role in gastric tumorigenesis itself.Successful H.pylori eradication is suggested to restore gastric microbiota,at least in primary stages.It is more than clear that Hp-I,gastric microbiota and gastric cancer constitute a challenging tangle and the strong interaction between them makes it difficult to unroll.Future studies are considered of crucial importance to test the complex interaction on the modulation of the gastric microbiota by H.pylori as well as on the relationships between the gastric microbiota and gastric carcinogenesis.

MicroRNA-feedback loop as a key modulator of liver tumorigenesis and inflammation

A recent work of Iliopoulos et al published in Cell highlighted a circuit orchestrated by microRNAs (miRNAs) that results in liver tumorigenesis and inflammation. This feedback loop, governed by miR-24 and miR-629, promotes a hepatocyte nuclear factor-4α transient inhibition resulting in miR-124 induction and signal transducer and activator of transcription 3 activation. These promising data support the use of miRNA mimics or inhibitors as potent therapeutic approaches in liver cancer.

“Identification Card”: Sites on Histone Modification of Cancer Cell

Formation of malignant tumor originating from normal healthy cell is a multistep process including genetic and epigenetic lesions. Previous studies of cell line model systems displayed that early important epigenetic events happened in stepwise fashion prior to cell immortalization. Once these epigenetic alterations are integrated into chromatin, they will perform vertical propagation through cell subculture. Hence, status of epigenetics is dramatically important in maintaining of cell identity. Histone modification is another factor of epigenetic alterations during human oncogenesis. Histones, one of main components of chromatin, can be modified post-translationally. Histone tail modifications are regulated by corresponding modification enzymes. This review focuses on the description of relationship between the main sites of histone modification and oncogenesis.

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

AIM To clarify the prevalence of occult hepatitis B virus(HBV) infection(OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma(HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus(HCV) infection. METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection(chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or moredifferent viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively(P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase > 40 IU/L, Child-Pugh score and sustained virologic response(SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.

Cell Signaling in Viral and Oncogenic Pathogenesis and Its Implications in Disease Diagnosis and Prognosis

Both viral diseases and cancer account for a large proportion of serious health problems. Viral infection and cancer are biologically and medically correlated and in many ways share common cellular pathways that lead to disease development or progression. Better understanding how these signaling events are specifically activated by different pathogenic stimuli and how they activate different downstream transcriptions in response to these stimuli at high specificity and efficiency will provide a new molecular basis for the development of novel disease biomarkers and therapeutic or preventive targets against both classes of diseases. Research in our laboratory has been prompted to investigate the regulation and modes of action of these pathways, with a more intensive focus on the NF-κB signaling, in the settings of severe or oncogenic viral infection as well as cancer development. It is hoped that our research will lead to eventual clinical application of biomarkers derived from these signaling pathways.

MicroRNA-188-5p targeting Forkhead Box L1 promotes colorectal cancer progression via activating Wnt/β-catenin signaling

Objective:MicroRNA-188-5p(miR-188)enhances oncologic progression in various human malignancies.This study aimed to explore its role in colorectal cancer(CRC).Materials and Methods:Human CRC tissues paired with normal tissues,and several CRC cell lines were utilized.Real-time quantitative PCR was applied to measure the expression of miR-188.Overexpression and knockdown were used to access the function of miR-188 and to investigate whether FOXL1/Wnt signaling mediates such function.The proliferation,migration and invasion of cancer cells were evaluated by CCK8,wound-healing and transwell assays,respectively.Whether FOXL1 acted as a direct target of miR-188 was verified by dual-luciferase reporter assays.Results:Levels of miR-188 were upregulated in CRC tissues than in paired-normal tissues,as well as in various CRC cell lines.High expression of miR-188 was strongly associated with advanced tumor stage,accompanied with significant tumor cell proliferation,invasion and migration.It was confirmed that FOXL1 played positive crosstalk between miR-188 regulation and downstream Wnt/β-catenin signaling activation.Conclusions:All findings indicate that miR-188 promotes CRC cell proliferation and invasion through targeting FOXL1/Wnt signaling and could be served as a potential therapeutic target for human CRC in the future.

Cancer and Infectious Causes

Various kinds of organisms, including viruses, bacteria, trematodes and fungi are known carcinogens that cause cancer. Infectious identification related to cancer may lead to better treatment for both the prevention and targeting of cancer therapy. Although nearly 20% of all cancers are caused by an infection of a microbe, the amount of evidence and information regarding the mechanisms associated with oncogenesis varies dramatically from one organism to the next. This review cannot be exhaustive because we are not aware of all infections worldwide in addition to their potential mechanisms for oncogenesis. More research is required for all of the species mentioned in this review.

Critical roles of non-coding RNAs in lifecycle and biology of Marek's disease herpesvirus

Over the past two decades, numerous non-coding RNAs(ncRNAs) have been identified in different biological systems including virology, especially in large DNA viruses such as herpesviruses. As a representative oncogenic alphaherpesvirus, Marek’s disease virus(MDV) causes an important immunosuppressive and rapid-onset neoplastic disease of poultry, namely Marek’s disease(MD). Vaccinations can efficiently prevent the onset of MD lymphomas and other clinical disease, often heralded as the first successful example of vaccination-based control of cancer. MDV infection is also an excellent model for research into virally-induced tumorigenesis. Recently, great progress has been made in understanding the functions of ncRNAs in MD biology.Herein, we give a review of the discovery and identification of MDV-encoded viral miRNAs, focusing on the genomics,expression profiles, and emerging critical roles of MDV-1 miRNAs as oncogenic miRNAs(oncomiRs) or tumor suppressor genes involved in the induction of MD lymphomas. We also described the involvements of host cellular miRNAs, lincRNAs, and circRNAs participating in MDV life cycle, pathogenesis, and/or tumorigenesis. The prospects, strategies, and new techniques such as the CRISPR/Cas9-based gene editing applicable for further investigation into the ncRNA-mediated regulatory mechanisms in MDV pathogenesis/oncogenesis were also discussed, together with the possibilities of future studies on antiviral therapy and the development of new efficient MD vaccines.

Targeting histone deacetylases for cancer therapy: Trends and challenges

Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. This review investigates the biological functions of HDACs, the roles of HDACs in oncogenesis, the structural features of different HDAC isoforms, isoform-selective inhibitors, combination therapies, multitarget agents and HDAC PROTACs. We hope these data could inspire readers with new ideas to develop novel HDACi with good isoform selectivity, efficient anticancer effect, attenuated adverse effect and reduced drug resistance.

PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities

The last few decades have witnessed an advancement in our understanding of multiple cancer cell pathways related to metabolic reprogramming.One of the most important cancer hallmarks,including aerobic glycolysis(the Warburg effect),the central carbon pathway,and multiple-branch metabolic pathway remodeling,enables tumor growth,progression,and metastasis.Phosphoenolpyruvate carboxykinase1(PCK1),a key rate-limiting enzyme in gluconeogenesis,catalyzes the conversion of oxaloacetate to phosphoenolpyruvate.PCK1 expression in gluconeogenic tissues is tightly regulated during fasting.In tumor cells,PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracellular environment.Interestingly,PCK1has ananti-oncogenic role in gluconeogenic organs(the liver and kidneys),but a tumor-promoting role in cancers arising from non-gluconeogenic organs.Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways.Aberrant PCK1 expression results in the activation of oncogenic pathways,accompanied by metabolic reprogramming,to maintain tumorigenesis.In this review,we summarize the mechanisms underlying PCK1 expression and regulation,and clarify the crosstalk between aberrant PCK1 expression,metabolic rewiring,and signaling pathway activation.In addition,we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.

Notch signaling:Its essential roles in bone and craniofacial development

Notch is a cellecell signaling pathway that is involved in a host of activities including development,oncogenesis,skeletal homeostasis,and much more.More specifically,recent research has demonstrated the importance of Notch signaling in osteogenic differentiation,bone healing,and in the development of the skeleton.The craniofacial skeleton is complex and understanding its development has remained an important focus in biology.In this review we briefly summarize what recent research has revealed about Notch signaling and the current understanding of how the skeleton,skull,and face develop.We then discuss the crucial role that Notch plays in both craniofacial development and the skeletal system,and what importance it may play in the future.

N^(6)-methyladenosine Steers RNA Metabolism and Regulation in Cancer

As one of the most studied ribonucleic acid(RNA)modifications in eukaryotes,N^(6)-methyladenosine(m^(6)A)has been shown to play a predominant role in controlling gene expression and influence physiological and pathological processes such as oncogenesis and tumor progression.Writer and eraser proteins,acting opposite to deposit and remove m^(6)A epigenetic marks,respectively,shape the cellular m^(6)A landscape,while reader proteins preferentially recognize m^(6)A modifications and mediate fate decision of the methylated RNAs,including RNA synthesis,splicing,exportation,translation,and stability.Therefore,RNA metabolism in cells is greatly influenced by these three classes of m^(6)A regulators.Aberrant expression of m^(6)A regulators has been widely reported in various types of cancer,leading to cancer initiation,progression,and drug resistance.The close links between m^(6)A and cancer shed light on the potential use of m^(6)A methylation and its regulators as prognostic biomarkers and drug targets for cancer therapy.Given the notable effects of m^(6)A in reversing chemoresistance and enhancing immune therapy,it is a promising target for combined therapy.Herein,we summarize the recent discoveries on m^(6)A and its regulators,emphasizing their influences on RNA metabolism,their dysregulation and impacts in diverse malignancies,and discuss the clinical implications of m^(6)A modification in cancer.

Activating transcription factor 3 in immune response and metabolic regulation

Activating transcription factor 3(ATF3)is a member of the ATF/cyclic adenosine monophosphate(cAMP)-response element binding protein(CREB)family of transcription factors.In response to stress stimuli,ATF3 forms dimers to activate or repress gene expression.Further,ATF3 modulates the immune response,atherogenesis,cell cycle,apoptosis,and glucose homeostasis.Recent studies have shown that ATF3 may also be involved in pathogenesis of other diseases.However,more studies are needed to determine the role of ATF3 in metabolic regulation.

How will telomeric complex be further contributed to our longevity?—The potential novel biomarkers of telomere complex counteracting both aging and cancer

With the smooth move towards the coming expected clinical reports of anticancer pharmaceutical molecules targeting telomeres and telomerase,and also with the exciting success in the extension of lifespan by regulating telomerase activity without increased onset of oncogenesis in laboratory mouse models(Garcia-Cao et al.,2006;Jaskelioff et al.,2011),we are convinced that targeting telomeres based on telomerase will be a potential approach to conquer both aging and cancer and the idea of longevity seems to be no more mysterious.More interestingly,emerging evidences from clinical research reveal that other telomeric factors,like specifi c telomeric binding proteins and nonspecific telomere associated proteins also show crucial importance in aging and oncogenesis.This stems from their roles in the stability of telomere structure and in the inhibition of DNA damage response at telomeres.Uncapping these proteins from chromosome ends leads to dramatic telomere loss and telomere dysfunction which is more abrupt than those induced by telomerase inactivation.Abnormal expression of these factors results in developmental failure,aging and even oncogenesis evidenced by several experimental models and clinical cases,indicating telomere specifi c proteins and its associated proteins have complimentary roles to telomerase in telomere protection and controlling cellular fate.Thus,these telomeric factors might be potential clinical biomarkers for early detection or even therapeutic targets of aging and cancer.Future studies to elucidate how these proteins function in telomere protection might benefit patients suffering aging or cancer who are not sensitive to telomerase mediation.

Impact of direct-acting antivirals on the recurrence of hepatocellular carcinoma in chronic hepatitis C

Chronic hepatitis C virus(HCV)infection is estimated to affect 56.8 million individuals globally and is a major and independent risk factor for the development of hepatocellular carcinoma(HCC).After the introduction of safe and potent direct-acting antivirals(DAAs),capable of curing HCV infection also in patients with advanced liver disease at high risk of HCC,the beneficial effect on a de novo HCC development after viral clearance has been established.However,studies addressing the relationship between DAA-induced eradication and risk of HCC recurrence(i.e.,reappearance of HCC treated before starting antivirals)have produced contradictory data,suggesting either an increase or a decrease of HCC recurrence rate,while some report no effect of these treatments.Thus,there seems to be an unclear benefit of viral clearance in patients with a history of HCC curative treatment,where the recurrence rate remains worryingly high.This short review aims to summarize current evidence on the impact of DAAs on HCC recurrence rates,the pathogenic mechanisms and characteristics of HCC recurrence after DAA treatment,the predictors of tumor recurrence,and the impact of DAAs on overall survival.

Direct acting antivirals therapy and hepatocellular carcinoma risk in patients with hepatitis C virus

The estimated number of people with active hepatitis C virus infection worldwide is about 70 million.The estimated number of people with active hepatitis C virus infection worldwide is about 70 million.Approximately 30%of infected individuals develop cirrhosis,whilst some develop liver cancer,the fifth most common cancer worldwide.Currently available treatments,high-efficacy antiviral agents mostly short-term(8-12 weeks)and pangenotypic,have efficacy rates of over 96%.Some patients,especially those with cirrhosis,develop primary liver cancer even after effective hepatitis C virus treatment.In order to diagnose hepatocellular carcinoma early,patients at risk should be enrolled in a surveillance program.