Exercise sustains the hallmarks of health

Exercise has long been known for its active role in improving physical fitness and sustaining health.Regular moderate-intensity exercise improves all aspects of human health and is widely accepted as a preventative and therapeutic strategy for various diseases.It is well-documented that exercise maintains and restores homeostasis at the organismal,tissue,cellular,and molecular levels to stimulate positive physiological adaptations that consequently protect against various pathological conditions.Here we mainly summarize how moderate-intensity exercise affects the major hallmarks of health,including the integrity of barriers,containment of local perturbations,recycling and turnover,integration of circuitries,rhythmic oscillations,homeostatic resilience,hormetic regulation,as well as repair and regeneration.Furthermore,we summarize the current understanding of the mechanisms responsible for beneficial adaptations in response to exercise.This review aimed at providing a comprehensive summary of the vital biological mechanisms through which moderate-intensity exercise maintains health and opens a window for its application in other health interventions.We hope that continuing investigation in this field will further increase our understanding of the processes involved in the positive role of moderate-intensity exercise and thus get us closer to the identification of new therapeutics that improve quality of life.

ABC transporters and the hallmarks of cancer:roles in cancer aggressiveness beyond multidrug resistance

The ATP-binding cassette transporters(ABC transporters)have been intensely studied over the past 50 years for their involvement in the multidrug resistance(MDR)phenotype,especially in cancer.They are frequently overexpressed in both naive and post-treatment tumors,and hinder effective chemotherapy by reducing drug accumulation in cancer cells.In the last decade however,several studies have established that ABC transporters have additional,fundamental roles in tumor biology;there is strong evidence that these proteins are involved in transporting tumor-enhancing molecules and/or in protein-protein interactions that impact cancer aggressiveness,progression,and patient prognosis.This review highlights these studies in relation to some well-described cancer hallmarks,in an effort to re-emphasize the need for further investigation into the physiological functions of ABC transporters that are critical for tum or development.Unraveling these new roles offers an opportunity to define new strategies and targets for therapy,which would include endogenous substrates or signaling pathways that regulate these proteins.

A multilevel pan-cancer map links gene mutations to cancer hallmarks

Background:A central challenge in cancer research is to create models that bridge the gap between the molecular level on which interventions can be designed and the cellular and tissue levels on which the disease phenotypes are manifested.This study was undertaken to construct such a model from functional annotations and explore its use when integrated with large-scale cancer genomics data.Methods:We created a map that connects genes to cancer hallmarks via signaling pathways.We projected gene mutation and focal copy number data from various cancer types onto this map.We performed statistical analyses to uncover mutually exclusive and co-occurring oncogenic aberrations within this topology.Results:Our analysis showed that although the genetic fingerprint of tumor types could be very different,there were less variations at the level of hallmarks,consistent with the idea that different genetic alterations have similar functional outcomes.Additionally,we showed how the multilevel map could help to clarify the role of infrequently mutated genes,and we demonstrated that mutually exclusive gene mutations were more prevalent in pathways,whereas many co-occurring gene mutations were associated with hallmark characteristics.Conclusions:Overlaying this map with gene mutation and focal copy number data from various cancer types makes it possible to investigate the similarities and differences between tumor samples systematically at the levels of not only genes but also pathways and hallmarks.

The systemic hallmarks of cancer

Cancer is not just a lump of cells that divide,invade,and spread randomly,but rather a multi-layered precisely tuned process that requires the participation of the whole organism.There is an urgent need to zoom-out from the cellular and the local stromal view and broaden our perspective by including the whole organism level.Geographically separated cancer tissues communicate between themselves,forming a system that interacts with the rest of the organism through cancer induced systemic pathogenic networks.In the present paper,I introduce six systemic hallmarks of cancer that emerge as a result of these interactions.I also describe several potential therapeutic approaches that can be developed using the cancer system concept.Overall,I argue that the tumoricentric paradigm should be replaced with a broader approach that brings into focus the“cancerized”organism.

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis,cancer,and liver failure.Liver cancer is the third leading cause of cancer-associated mortality,of which hepatocellular carcinoma(HCC)represents 90%of all primary liver cancers.Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management.Chronic infection with hepatitis B virus(HBV),hepatitis delta virus(HDV),and hepatitis C virus(HCV)are the greatest etiological risk factors for HCC.Due to the significant role of chronic viral infection in HCC development,it is important to investigate direct(viral associated)and indirect(immune-associated)mechanisms involved in the pathogenesis of HCC.Common mechanisms used by HBV,HCV,and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response,immune and viral protein-mediated oxidative stress,and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection,and metabolic reprogramming leading to steatosis is driven by HCV infection.The current review aims to provide a brief overview of HBV,HCV and HDV molecular biology,and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC,and current as well as emerging treatments for HCC.

Effect of oridonin-mediated hallmark changes on inflammatory pathways in human pancreatic cancer(BxPC-3) cells

AIM:To investigate the effect of oridonin on nuclear transcription factors and to study the relationship between biological behavior and inflammatory factors in human pancreatic cancer(BxPC-3)cells.METHODS:BxPC-3 cells were treated with various concentrations of oridonin,and viability curves were generated to test for inhibitory effects of the drug on cells.The expression of cytokines such as interleukin-1β(IL-1β),IL-6,or IL-33 was detected in BxPC-3 cell supernatants using an enzyme-linked immunosorbent assay(ELISA),and the protein expression of nuclear transcription factors including nuclear factorκB,activating protein-1,signal transducer and activator of transcription 3,bone morphogenetic protein 2,trans-forming growth factorβ1 and sma and mad homologues in BxPC-3 cells was detected using Western blot.Carcinoma hallmark-related proteins such as survivin,vascular endothelial growth factor,and matrix metallopeptidase 2 were also detected using immunoblotting,and intra-nuclear IL-33 expression was detected using immunofluorescent staining.RESULTS:Treatment with oridonin reduced the viability of BxPC-3 cells in a dose dependent manner.The cells exhibited reduced growth following treatment with 8μg/mL oridonin(13.05%±3.21%,P<0.01),and the highest inhibitory ratio was 90.64%±0.70%,which was achieved with oridonin at a dose of32μg/mL.The IC50 value of oridonin in BxPC-3 cells was 19.32μg/mL.ELISA analysis revealed that oridonin down-regulated the inflammatory factors IL-1β,IL-6,and IL-33 in a dose-dependent manner.IL-1βexpression was significantly reduced in the 16 and 32μg/mL treatment groups compared to the control group(12.97±0.45 pg/mL,11.17±0.63 pg/mL vs 14.40±0.38pg/mL,P<0.01).Similar trends were observed for IL-6expression,which was significantly reduced in the 16and 32μg/mL treatment groups compared to the control group(4.05±0.14 pg/mL vs 4.45±0.43 pg/mL,P<0.05;3.95±0.13 pg/mL vs 4.45±0.43 pg/mL,P<0.01).IL-33 expression was significantly reduced in the8,16,and 32μg/mL treatment groups compared to the control group(911.05±14.18 pg/mL vs 945.25±12.09 pg/mL,P<0.05;802.70±11.88 pg/mL,768.54±10.98 pg/mL vs 945.25±12.09 pg/mL,P<0.01).Western blot and immunofluorescent staining analyses suggested that oridonin changed the hallmarks and regulated the expression of various nuclear transcription factors.CONCLUSION:The results obtained suggest that oridonin alters the hallmarks of pancreatic cancer cells through the regulation of nuclear transcription factors.

Microbiome and colorectal carcinogenesis:Linked mechanisms and racial differences

Various studies have shown the interplay between the intestinal microbiome,environmental factors,and genetic changes in colorectal cancer(CRC)development.In this review,we highlight the various gut and oral microbiota associated with CRC and colorectal adenomas,and their proposed molecular mechanisms in relation to the processes of“the hallmarks of cancer”,and differences in microbial diversity and abundance between race/ethnicity.Patients with CRC showed increased levels of Bacteroides,Prevotella,Escherichia coli,enterotoxigenic Bacteroides fragilis,Streptococcus gallolyticus,Enterococcus faecalis,Fusobacterium nucleatum(F.nucleatum)and Clostridium difficile.Higher levels of Bacteroides have been found in African American(AA)compared to Caucasian American(CA)patients.Pro-inflammatory bacteria such as F.nucleatum and Enterobacter species were significantly higher in AAs.Also,AA patients have been shown to have decreased microbial diversity compared to CA patients.Some studies have shown that using microbiome profiles in conjunction with certain risk factors such as age,race and body mass index may help predict healthy colon vs one with adenomas or carcinomas.Periodontitis is one of the most common bacterial infections in humans and is more prevalent in Non-Hispanic-Blacks as compared to Non-Hispanic Whites.This condition causes increased systemic inflammation,immune dysregulation,gut microbiota dysbiosis and thereby possibly influencing colorectal carcinogenesis.Periodontal-associated bacteria such as Fusobacterium,Prevotella,Bacteroides and Porphyromonas have been found in CRC tissues and in feces of CRC patients.Therefore,a deeper understanding of the association between oral and gastrointestinal bacterial profile,in addition to identifying prevalent bacteria in patients with CRC and the differences observed in ethnicity/race,may play a pivotal role in predicting incidence,prognosis,and lead to the development of new treatments.

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A Hallmark of Information Exchange and Technical Cooperation

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Oncogenic MORC2 in cancer development and beyond

Microrchidia CW-type zinc finger 2(MORC2)is a member of the MORC superfamily of nuclear proteins.Growing evidence has shown that MORC2 not only participates in gene transcription and chromatin remodeling but also plays a key in human disease and tumor development by regulating the expression of downstream oncogenes or tumor suppressors.The present review provides an updated overview of MORC2 in the aspect of cancer hallmark and therapeutic resistance and summarizes its upstream regulators and downstream target genes.This systematic review may provide a favorable theoretical basis for emerging players of MORC2 in tumor development and new insight into the potential clinical application of basic science discoveries in the future.

An Integrative Meta-analysis of MicroRNAs in Hepatocellular Carcinoma

We aimed to shed new light on the roles of microRNAs （miRNAs） in liver cancer using an integrative in silico bioinformatics analysis. A new protocol for target prediction and functional analysis is presented and applied to the 26 highly differentially deregulated miRNAs in hepatocellular carcinoma. This framework comprises： （1） the overlap of prediction results by four out of five target prediction tools, including TargetScan, PicTar, miRanda, DIANA-microT and miRDB （combining machine-learning, alignment, interaction energy and statistical tests in order to minimize false positives）, （2） evidence from previous microarray analysis on the expression of these targets, （3） gene ontology （GO） and pathway enrichment analysis of the miRNA targets and their pathways and （4） linking these results to oncogenesis and cancer hallmarks. This yielded new insights into the roles of miRNAs in cancer hallmarks. Here we presented several key targets and hundreds of new targets that are significantly enriched in many new cancer-related hallmarks. In addition, we also revealed some known and new oncogenic pathways for liver cancer. These included the famous MAPK, TGFβ and cell cycle pathways. New insights were also provided into Wnt signaling, prostate cancer, axon guidance and oocyte meiosis pathways. These signaling and developmental pathways crosstalk to regulate stem cell transformation and implicate a role of miRNAs in hepatic stem cell deregulation and cancer development. By analyzing their complete interactome, we proposed new categorization for some of these miRNAs as either tumor-suppressors or oncomiRs with dual roles. Therefore some of these miRNAs may be addressed as therapeutic targets or used as therapeutic agents. Such dual roles thus expand the view of miRNAs as active maintainers of cellular homeostasis.

Overview of genetic signaling pathway interactions within cutaneous malignancies

Melanoma and non-melanoma cutaneous malignancies are some of the leading causes of cancer-related death in the United States.Though melanoma is more known to have a high mortality rate,the total mortality per year is nearly equal for between melanoma and non-melanoma skin cancer.Moreover,the non-melanoma types of cutaneous malignancies have potential to become locally invasive and even metastasize with very little to no treatment options when advanced.The development of these malignancies involves various genetic pathways through the four hallmarks of cancer development:malignant cell growth,apoptosis evasion,the use of supporting stroma and vascularization,and modulating and promoting an inadequate immune response.The genetic signaling pathways of basal cell carcinoma,squamous cell carcinoma,verrucous carcinoma,basosquamous cell carcinoma,melanoma,and cutaneous T-cell lymphoma interact with each other through genetic predisposition as well as with environmental exposures.Furthermore,solar ultraviolet radiation and chronic inflammatory states are found to initiate the progression of many of these cutaneous malignancies.This paper includes validated models of genetic pathways,emerging pathways,and crosstalk between genetic pathways through the four hallmarks of cancer development.Moreover,unlike most reviews addressing oncogenetics of the well-recognized,as well as newly discovered,genetic pathway mutations,this review stresses that these pathways are not fixed but rather exist in dynamic,interrelated,interactive,complex,and adaptive flux states.

Significance of alternative splicing in cancer cells

Objective:Alternative splicing can generate various structural and functional protein isoforms.Recently,accumulating evidence shows a relationship between alternative splicing and cancer.Cancer is a complex and chronic disease that involves malignant transformation.In this review,we consider alternative splicing events in relation to the hallmarks of cancer cells,and discuss current therapies to treat cancer-related to alternative splicing.Data sources:Data cited in this article are from the PubMed and Embase database,primarily focusing on research published from 2000 to 2018.Study selection:Articles were selected with the search terms“alternative splicing,”“cancer cell,”“tumor microenvironment,”and“therapy.”Results:Alternative splicing plays an important role in tumorigenesis,development,and escape from cell death.Taking this trait of cancer cells into consideration will allow more definite diagnoses of cancer,and allow the development of more effective medicines to intervene in cancer that could focus on controlling alternative splicing or competitively binding to the final products.Conclusions:Alternative splicing is common in cancer cells.Consideration of alternative splicing may allow different strategies for cancer therapy or the identification of novel biomarkers for cancer diagnosis.