Toll-like receptor signaling in colorectal cancer:carcinogenesis to cancer therapy

Toll-like receptors(TLRs)are germ line encoded innate immune sensors that recognize conserved microbial structures and host alarmins,and signal expression of major histocompatibility complex proteins,costimulatory molecules,and inflammatory mediators by macrophages,neutrophils,dendritic cells,and other cell types.These protein receptors are characterized by their ability to respond to invading pathogens promptlyby recognizing particular TLR ligands,including flagellin and lipopolysaccharide of bacteria,nucleic acids derived from viruses,and zymosan of fungi.There are2 major TLR pathways;one is mediated by myeloid differentiation factor 88(MYD88)adaptor proteins,and the other is independent of MYD88.The MYD88-dependent pathway involves early-phase activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NF-κB1)and all the TLRs,except TLR3,have been shown to activate this pathway.TLR3and TLR4 act via MYD88-independent pathways with delayed activation of NF-κB signaling.TLRs play a vital role in activating immune responses.TLRs have been shown to mediate inflammatory responses and maintain epithelial barrier homeostasis,and are highly likely to be involved in the activation of a number of pathways following cancer therapy.Colorectal cancer(CRC)is one of the most common cancers,and accounts for almost half a million deaths annually worldwide.Inflammation is considered a risk factor for many common malignancies including cancers of the colorectum.The key molecules involved in inflammation-driven carcinogenesis include TLRs.As sensors of cell death and tissue remodeling,TLRs may have a universal role in cancer;stimulation of TLRs to activate the innate immune system has been a legitimate therapeutic strategy for some years.TLRs 3/4/7/8/9 are all validated targets for cancer therapy,and a number of companies are developing agonists and vaccine adjuvants.On the other hand,antagonists may favor inhibition of signaling responsible for autoimmune responses.In this paper,we review TLR signaling in CRC from carcinogenesis to cancer therapy.

IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions

AIM:To investigate insulin-like growth factor 2(IGF2)differentially methylated region(DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions.METHODS:To accurately analyze the association between the histological types and molecular features of each type of serrated lesion,we consecutively collected1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types[hyperplastic polyps(HPs,n=121),sessile serrated adenomas(SSAs,n=132),traditional serrated adenomas(TSAs,n=111),non-serrated adenomas(n=195),and colorectal cancers(n=827)].We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1(LINE-1)in HPs(n=115),SSAs(n=120),SSAs with cytological dysplasia(n=10),TSAs(n=91),TSAs with high-grade dysplasia(HGD)(n=15),non-serrated adenomas(n=80),non-serrated adenomas with HGD(n=105),and CRCs(n=794).For the accurate quantification of the relative methylation levels(scale 0%-100%)of IGF2 DMR0 and LINE-1,we used bisulfite pyrosequencing method.Tumor specimens were analyzed for microsatellite instability,KRAS(codons 12 and 13),BRAF(V600E),and PIK3CA(exons 9and 20)mutations;MLH1 and MGMT methylation;and IGF2 expression by immunohistochemistry.RESULTS:The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas(with or without HGD)was as follows:mean61.7,median 62.5,SD 18.0,range 5.0-99.0,interquartile range 49.5-74.4.The IGF2 DMR0 methylation level was divided into quartiles(Q1≥74.5,Q2 62.6-74.4,Q3 49.6-62.5,Q4≤49.5)for further analysis.With regard to the histological type,the IGF2 DMR0 methylation levels of SSAs(mean±SD,73.1±12.3)were significantly higher than those of HPs(61.9±20.5),TSAs(61.6±19.6),and non-serrated adenomas(59.0±15.8)(P<0.0001).The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level(r=-0.21,P=0.0051).IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs,TSAs,and non-serrated adenomas(P<0.0001).Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs(P<0.0001).The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD(50.2±18.7and 55.7±5.4,respectively)were significantly lower than those in TSAs(61.6±19.6 and 58.8±4.7,respectively)(IGF2 DMR0,P=0.038;LINE-1,P=0.024).CONCLUSION:IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway.Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression.