Genetic Polymorphisms in Inflammatory and Other Regulators in Gastric Cancer: Risks and Clinical Consequences

Zhao²,

BMC Complement Altern Med

et al. 2019

BackgroundAltered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4–17, 2014; Kim and Bae, Curr Opin Hematol 25:52–59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism.MethodsFirstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a−/− mouse model (Spicer etal., J Biol Chem 275:21555–21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a−/−mice.ResultsIn this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a−/− mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05).ConclusionsConclusively, WPL could ameliorate GPLs in Atp4a−/− mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Weipiling ameliorates gastric precancerous lesions in Atp4a−/− mice

Zhao²,

BMC Complement Altern Med

et al. 2019

“…The majority of H. pylori-infected individuals remain asymptomatic, but even in these subjects, infection increases the risk of serious diseases. A total of 10% to 15% of H. pylori-infected individuals develop chronic inflammatory responses, which correlate with an increased risk of gastric and duodenal ulcers, stomach cancer and mucosa-associated lymphoid tissue (MALT) lymphoma [7][8][9][10][11][12][13]. Chronic colonization of the gastric mucosa by H. pylori and long-lasting interaction between bacteria and their soluble or cell-bound components as well as gastric epithelial cells determine the pathogenic process [10,14,15].…”

Section: Introductionmentioning

confidence: 99%

Proregenerative Activity of IL-33 in Gastric Tissue Cells Undergoing Helicobacter Pylori-Induced Apoptosis

Gonciarz

Krupa

Chmiela

2020

IJMS

Self Cite

Interleukin (IL)-33 is a proinflammatory mediator that alerts the host immune system to disorders in tissue homeostasis. Aim. To understand the role of IL-33 in modulating gastric tissue cell growth affected by Helicobacter pylori (H. pylori). Methods. IL-33 production in guinea pigs (Caviae porcellus) experimentally infected with H. pylori was evaluated by ELISA or immunohistochemical staining. The proregenerative activity of IL-33 was evaluated using gastric epithelial cells and fibroblasts that were naive or transfected with IL-33 siRNA exposed to H. pylori glycine acid extract antigenic complex (GE), as well as by measuring cell migration, proliferation, metabolic activity and apoptosis. Animals infected by H. pylori responded with increased production of IL-33. Also, cells treated in vitro with GE released more IL-33 than cells that were unstimulated. Silencing IL-33 in cells resulted in downregulation of metabolic activity, adhesion, migration and proliferation, especially after treatment with H. pylori GE, as well as upregulation of cells apoptosis associated with caspase 3 increase and Bcl-xL decrease, suggesting proregenerative activity of IL-33. Interestingly, upregulation of cell proliferation by IL-33 was Erk independent. Our results indicate that IL-33 may protect gastric tissue from loss of homeostasis caused by deleterious effects of H. pylori components and the inflammatory response developed during infection.

“…Like all meta-analyses, this study also has some limitations. First, the pooled results regarding associations between polymorphisms in CTLA-4/MBL/IL-4/IL-6/PLCE1 and GC were based on combining unadjusted findings of eligible studies due to lack of raw data 27. Second, the relationship between polymorphisms in CTLA-4/MBL/IL-4/IL-6/PLCE1 and GC may also be affected by environmental factors.…”

Section: Discussionmentioning

confidence: 99%

Estimation of associations between 10 common gene polymorphisms and gastric cancer: evidence from a meta-analysis

et al. 2019

AimsAssociations between polymorphisms in cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)/mannose-binding lectin (MBL)/interleukin-4 (IL-4)/interleukin-6 (IL-6)/phospholipase C ε−1 (PLCE1) and gastric cancer (GC) were already reported by many studies, yet the conclusions of these studies were somehow controversial. The aim of this meta-analysis was to better clarify associations between polymorphisms in CTLA-4/MBL/IL-4/IL-6/PLCE1 and GC by combing the results of all relevant studies.MethodsEligible studies were searched from PubMed, Embase, WOS and CNKI. We used Review Manager to combine the results of individual studies.ResultsForty-three studies were included in this meta-analysis. Combined results revealed that CTLA-4 rs5742909 (dominant comparison: OR: 1.58, 95 % CI: 1.01 to 2.48; allele comparison: OR: 1.69, 95 % CI: 1.12 to 2.56) and PLCE1 rs2274223 (dominant comparison: OR: 0.84, 95 % CI: 0.72 to 0.98; recessive comparison: OR: 1.23, 95 % CI: 1.08 to 1.40; over-dominant comparison: OR: 1.16, 95 % CI: 1.00 to 1.34; allele comparison: OR 0.88, 95 % CI 0.78 to 0.99) polymorphisms were significantly associated with GC in the general population. We also obtained similar significant associations with GC for rs5742909 and rs2274223 polymorphisms in East Asians. Nevertheless, no positive results were observed for the other eight investigated polymorphisms.ConclusionCollectively, this meta-analysis demonstrated that CTLA-4 rs5742909 and PLCE1 rs2274223 polymorphisms may confer susceptibility to GC, especially for East Asians.