Deciphering gastric inflammation-induced tumorigenesis through multi-omics data and AI methods

Gastric cancer(GC), the fifth most common cancer globally, remains the leading cause of cancer deaths worldwide. Inflammation-induced tumorigenesis is the predominant process in GC development;therefore, systematic research in this area should improve understanding of the biological mechanisms that initiate GC development and promote cancer hallmarks. Here, we summarize biological knowledge regarding gastric inflammation-induced tumorigenesis, and characterize the multi-omics data and systems biology methods for investigating GC development. Of note, we highlight pioneering studies in multi-omics data and state-of-the-art network-based algorithms used for dissecting the features of gastric inflammation-induced tumorigenesis, and we propose translational applications in early GC warning biomarkers and precise treatment strategies. This review offers integrative insights for GC research, with the goal of paving the way to novel paradigms for GC precision oncology and prevention.

Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines

Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout（omentin-1^-/-） mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-α（TNF-α）, we determined that recombinant omentin-1 reduces the production of proinflammatory factors in the TNF-α-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate-induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the proinflammatory cytokines.

Expression of the methylcytosine dioxygenase ten-eleven translocation-2 and connexin 43 in inflammatory bowel disease and colorectal cancer

BACKGROUND Inflammatory bowel disease(IBD)constitutes a substantial risk factor for colorectal cancer.Connexin 43(Cx43)is a protein that forms gap junction(GJ)complexes involved in intercellular communication,and its expression is altered under pathological conditions,such as IBD and cancer.Recent studies have implicated epigenetic processes modulating DNA methylation in the pathogenesis of diverse inflammatory and malignant diseases.The ten-eleven translocation-2(TET-2)enzyme catalyzes the demethylation,hence,regulating the activity of various cancer-promoting and tumor-suppressor genes.AIM To investigate Cx43 and TET-2 expression levels and presence of 5-hydroxymethylcytosine(5-hmC)marks under inflammatory conditions both in vitro and in vivo.METHODS TET-2 expression was evaluated in parental HT-29 cells and in HT-29 cells expressing low or high levels of Cx43,a putative tumor-suppressor gene whose expression varies in IBD and colorectal cancer,and which has been implicated in the inflammatory process and in tumor onset.The dextran sulfate sodium-induced colitis model was reproduced in BALB/c mice to evaluate the expression of TET-2 and Cx43 under inflammatory conditions in vivo.In addition,archived colon tissue sections from normal,IBD(ulcerative colitis),and sporadic colon adenocarcinoma patients were obtained and evaluated for the expression of TET-2 and Cx43.Expression levels were reported at the transcriptional level by quantitative real-time polymerase chain reaction,and at the translational level by Western blotting and immunofluorescence.RESULTS Under inflammatory conditions,Cx43 and TET-2 expression levels increased compared to noninflammatory conditions.TET-2 upregulation was more pronounced in Cx43-deficient cells.Moreover,colon tissue sections from normal,ulcerative colitis,and sporadic colon adenocarcinoma patients corroborated that Cx43 expression increased in IBD and decreased in adenocarcinoma,compared to tissues from non-IBD subjects.However,TET-2 expression and 5-hmC mark levels decreased in samples from patients with ulcerative colitis or cancer.Cx43 and TET-2 expression levels were also investigated in an experimental colitis mouse model.Interestingly,mice exposed to carbenoxolone(CBX),a GJ inhibitor,had upregulated TET-2 levels.Collectively,these results show that TET-2 levels and activity increased under inflammatory conditions,in cells downregulating gap junctional protein Cx43,and in colon tissues from mice exposed to CBX.CONCLUSION These results suggest that TET-2 expression levels,as well as Cx43 expression levels,are modulated in models of intestinal inflammation.We hypothesize that TET-2 may demethylate genes involved in inflammation and tumorigenesis,such as Cx43,potentially contributing to intestinal inflammation and associated carcinogenesis.

Fusobacterium nucleatum promotes colon cancer progression by changing the mucosal microbiota and colon transcriptome in a mouse model

BACKGROUND Fusobacterium nucleatum(F.nucleatum)has long been known to cause opportunistic infections and has recently been implicated in colorectal cancer(CRC),which has attracted broad attention.However,the mechanism by which it is involved in CRC development is not fully understood.AIM To explore its potential causative role in CRC development,we evaluated the colon pathology,mucosa barrier,colon microbiota and host transcriptome profile after F.nucleatum infection in an azoxymethane/dextran sulfate sodium salt(AOM/DSS)mouse model.METHODS Three groups of mice were compared to reveal the differences,i.e.,the control,AOM/DSS-induced CRC and AOM/DSS-FUSO infection groups.RESULTS Both the AOM/DSS and AOM/DSS-FUSO groups exhibited a significantly reduced body weight and increased tumor numbers than the control group,and AOM/DSS mice with F.nucleatum infection showed the highest tumor formation ratio among the three groups.Moreover,the colon pathology was the most serious in the AOM/DSS-FUSO group.We found that the structure of the colon microbiota changed considerably after F.nucleatum infection;striking differences in mucosal microbial population patterns were observed between the AOM/DSS-FUSO and AOM/DSS groups,and inflammation-inducing bacteria were enriched in the mucosal microbiota in the AOM/DSS-FUSO group.By comparing intestinal transcriptomics data from AOM vs AOM/DSSFUSO mice,we showed that transcriptional activity was strongly affected by dysbiosis of the gut microbiota.The most microbiota-sensitive genes were oncogenes in the intestine,and the cyclic adenosine monophosphate signaling pathway,neuroactive ligand–receptor interaction,PPAR signaling pathway,retinol metabolism,mineral absorption and drug metabolism were highly enriched in the AOM/DSS-FUSO group.Additionally,we showed that microbial dysbiosis driven by F.nucleatum infection enriched eight taxa belonging to Proteobacteria,which correlates with increased expression of oncogenic genes.CONCLUSION Our study demonstrated that F.nucleatum infection altered the colon mucosal microbiota by enriching pathogens related to the development of CRC,providing new insights into the role of F.nucleatum in the oncogenic microbial environment of the colon.

Multidimensional Analgesia of Acupuncture by Increasing Expression of MD2 in Central Nervous System

Objective:To investigate changes of myeloid differentiation factor 2(MD2)in inflammation-induced pain and acupuncture-mediated analgesia.Methods:Mice were randomly divided into three groups by a random number table method:saline group(n=16),complete Freund's adjuvant(CFA)group(n=24)and CFA+electroacupuncture(EA)group(n=26).Inflammation-induced pain was modelled by injecting CFA to the plantar surface of the hind paw of mice and EA was applied to bilateral Zusanli(ST 36)to alleviate pain.Only mice in the CFA+EA group received EA treatment(30 min/d for 2 weeks)24 h after modelling.Mice in the saline and CFA groups received sham EA.von-Frey test and Hargreaves test were used to assess the pain threshold.Brain and spinal tissues were collected for immunofluorescence staining or Western blotting to quantify changes of MD2 expression.Results:CFA successfully induced plantar pain and EA significantly alleviated pain 3 days after modelling(P<0.01).Compared with the CFA group,the number of MD2*/c-fos* neurons was significantly increased in the dorsal horn of the spinal cord 7 and 14 days after EA,especially in laminae Ⅰ-Ⅱ。(P<0.01).The proportion of double positive cells to the number of c-fos positive cells and the mean fluorescence intensity of MD2 neurons were also significantly increased in laminae Ⅰ-Ⅱ。(P<0.01).Western blotting showed that the level of MD2 was significantly decreased by EA only in the hippocampus on day 7 and 14(both P<0.01)and no significant changes were observed in the cortex,thalamus,cerebellum,or the brainstem(P>0.05).Fluorescence staining showed significant decrease in the level of MD2 in periagueductal gray(PAG)and locus coeruleus(LC)after CFA injection on day 7(P<0.01 for PAG,P<0.05 for LC)and EA significantly reversed this decrease(P<0.01 for PAG,P<0.05 for LC).Conclusion:The unique changes of MD2 suggest that EA may exert the analgesic effect through modulating neuronal activities of the superficial laminae of the spinal cord and certain regions of the brain.

Dysfunction of PLA2G6 and CYP2C44-associated network signals imminent carcinogenesis from chronic inflammation to hepatocellular carcinoma

Little is known about how chronic inflammation contributes to the progression of hepatoceUular carcinoma （HCC）, especially the initiation of cancer. To uncover the critical transition from chronic inflammation to HCC and the molecular mechanisms at a network level, we analyzed the time-series proteomic data of woodchuck hepatitis virus/c.myc mice and age-matched wt-C57BL/6 mice using our dynamical network biomarker （DNB） model. DNB analysis indicated that the 5th month after birth of transgenic mice was the critical period of cancer initiation, just before the critical transition, which is consistent with clinical symptoms. Meanwhile, the DNB-associated network showed a drastic inversion of protein expression and coexpression levels before and after the critical transition. Two members of DNB, PLA2G6 and CYP2C44, along with their associated differentially expressed proteins, were found to induce dysfunction of arachidonic acid metabolism, further activate inflammatory responses through inflammatory mediator regulation of transient receptor potential channels, and finally lead to impairments of liver detoxification and malignant transition to cancer. As a c-Myc target, PLA2G6 positively correlated with c-Myc in expression, showing a trend from decreasing to increasing during carcinogenesis, with the minimal point at the critical transition or tipping point. Such trend of homologous PLA2G6 and c-Myc was also observed during human hepatocarcinogenesis, with the minimal point at high-grade dysplastic nodules （a stage just before the carcinogenesis）. Our study implies that PLA2G6 might function as an oncogene like famous c-Myc during hepatocar- cinogenesis, while downregulation of PLA2G6 and c-Myc could be a warning signal indicating imminent carcinogenesis.