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1.
Gut ; 69(9): 1572-1580, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-31974133

RESUMO

OBJECTIVE: Helicobacter pylori is associated with gastric inflammation, precancerous gastric atrophy (GA) and intestinal metaplasia (IM). We aimed to identify microbes that are associated with progressive inflammation, GA and IM 1 year after H. pylori eradication. DESIGN: A total of 587 H. pylori-positive patients were randomised to receive H. pylori eradication therapy (295 patients) or placebo (292 patients). Bacterial taxonomy was analysed on 404 gastric biopsy samples comprising 102 pairs before and after 1 year H. pylori eradication and 100 pairs before and after 1 year placebo by 16S rRNA sequencing. RESULTS: Analysis of microbial sequences confirmed the eradication of H. pylori in treated group after 1 year. Principal component analysis revealed distinct microbial clusters reflected by increase in bacterial diversity (p<0.00001) after H. pylori eradication. While microbial interactions remained largely unchanged after placebo treatment, microbial co-occurrence was less in treated group. Acinetobacter lwoffii, Streptococcus anginosus and Ralstonia were enriched while Roseburia and Sphingomonas were depleted in patients with persistent inflammation 1 year after H. pylori eradication. A distinct cluster of oral bacteria comprising Peptostreptococcus, Streptococcus, Parvimonas, Prevotella, Rothia and Granulicatella were associated with emergence and persistence of GA and IM. Probiotic Faecalibacterium praustznii was depleted in subjects who developed GA following H. pylori eradication. Functional pathways including amino acid metabolism and inositol phosphate metabolism were enriched while folate biosynthesis and NOD-like receptor signalling decreased in atrophy/IM-associated gastric microbiota. CONCLUSION: This study identified that gastric microbes contribute to the progression of gastric carcinogenesis after H. pylori eradication.


Assuntos
Bactérias , Gastrite Atrófica , Infecções por Helicobacter , Helicobacter pylori , Metaplasia , Estômago , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/patogenicidade , Biópsia/métodos , Biópsia/estatística & dados numéricos , Carcinogênese , Erradicação de Doenças/métodos , Erradicação de Doenças/estatística & dados numéricos , Progressão da Doença , Feminino , Gastrite Atrófica/microbiologia , Gastrite Atrófica/patologia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Metaplasia/microbiologia , Metaplasia/patologia , Interações Microbianas/efeitos dos fármacos , Pessoa de Meia-Idade , Análise de Sequência de RNA/métodos , Estômago/microbiologia , Estômago/patologia
2.
Oncogene ; 42(8): 601-612, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36564468

RESUMO

The incidence of colorectal cancer (CRC) is rising worldwide. Here, we identified SCNN1B as an outlier down-regulated in CRC and it functions as a tumor suppressor. SCNN1B mRNA and protein expression were down-regulated in primary CRC and CRC cells. In a tissue microarray cohort (N = 153), SCNN1B protein was an independent prognostic factor for favorable outcomes in CRC. Ectopic expression of SCNN1B in CRC cell lines suppressed cell proliferation, induced apoptosis, and cell cycle arrest, and suppressed cell migration in vitro. Xenograft models validated tumor suppressive function of SCNN1B in vivo. Mechanistically, Gene Set Enrichment Analysis (GSEA) showed that SCNN1B correlates with KRAS signaling. Consistently, MAPK qPCR and kinase arrays revealed that SCNN1B suppressed MAPK signaling. In particular, SCNN1B overexpression suppressed p-MEK/p-ERK expression and SRE-mediated transcription activities, confirming blockade of Ras-Raf-MEK-ERK cascade. Mechanistically, SCNN1B did not affect KRAS activation, instead impairing activation of c-Raf by inducing its inhibitory phosphorylation and targeting active c-Raf for degradation. The ectopic expression of c-Raf fully rescued cell proliferation and colony formation in SCNN1B-overexpressing CRC cells, confirming c-Raf as the principal molecular target of SCNN1B. In summary, we identified SCNN1B as a tumor suppressor by functioning as a c-Raf antagonist, which in turn suppressed oncogenic MEK-ERK signaling.


Assuntos
Neoplasias Colorretais , Sistema de Sinalização das MAP Quinases , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Canais Epiteliais de Sódio/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais , Canais de Sódio/metabolismo
3.
Nat Commun ; 13(1): 3971, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803966

RESUMO

Therapeutic targeting of KRAS-mutant colorectal cancer (CRC) is an unmet need. Here, we show that Proprotein Convertase Subtilisin/Kexin type 9 (PSCK9) promotes APC/KRAS-mutant CRC and is a therapeutic target. Using CRC patient cohorts, isogenic cell lines and transgenic mice, we identify that de novo cholesterol biosynthesis is induced in APC/KRAS mutant CRC, accompanied by increased geranylgeranyl diphosphate (GGPP)─a metabolite necessary for KRAS activation. PCSK9 is the top up-regulated cholesterol-related gene. PCSK9 depletion represses APC/KRAS-mutant CRC cell growth in vitro and in vivo, whereas PCSK9 overexpression induces oncogenesis. Mechanistically, PCSK9 reduces cholesterol uptake but induces cholesterol de novo biosynthesis and GGPP accumulation. GGPP is a pivotal metabolite downstream of PCSK9 by activating KRAS/MEK/ERK signaling. PCSK9 inhibitors suppress growth of APC/KRAS-mutant CRC cells, organoids and xenografts, especially in combination with simvastatin. PCSK9 overexpression predicts poor survival of APC/KRAS-mutant CRC patients. Together, cholesterol homeostasis regulator PCSK9 promotes APC/KRAS-mutant CRC via GGPP-KRAS/MEK/ERK axis and is a therapeutic target.


Assuntos
Neoplasias Colorretais , Pró-Proteína Convertase 9 , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Colesterol , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno , Pró-Proteína Convertase 9/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
4.
Theranostics ; 9(21): 6256-6268, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534549

RESUMO

Rationale: Prostaglandin E2 (PGE2) is a pro-inflammatory eicosanoid up-regulated in gastric cancer (GC). However, its impact on epigenetic dysfunction in the process of gastric carcinogenesis is unknown. In this study, we investigate the role of PGE2 in DNA methylation in gastric epithelium in vitro, in mice, and humans. Methods: PGE2-induced DNMT3B and DNA methylation was determined in gastric cell lines and COX-2 transgenic mice. Effect of COX-2 inhibition on DNA methylation was evaluated in a randomized controlled trial. Efficacy of combined COX-2/PGE2 and DNMT inhibition on GC growth was examined in cell lines and mice models. Results: PCR array analysis of PGE2-treated GC cells revealed the up-regulation of DNMT3B, a de novo DNA methyltransferase. In GC cells, PGE2 induced DNMT3B expression and activity, leading to increased methylated cytosine (5mC) and promoter methylation of tumor suppressive genes (MGMT and CNR1). Consistently, Cox-2 (rate-limiting enzyme for PGE2 biosynthesis) transgenic expression in mice significantly induced Dnmt3b expression, increased 5mC content, and promoted Mgmt promoter methylation. We retrospectively analyzed the 5mC content of 42 patients with intestinal metaplasia (a precancerous lesion of GC) treated with a COX-2 specific inhibitor Rofecoxib or placebo for 2 years, revealing that the COX-2 inhibitor significantly down-regulated 5mC levels (N=42, P=0.009). Collectively, these data indicate that PGE2 is closely related to DNA hypermethylation in vitro and in vivo. Using genome-wide 450K methylation array, we identified chromosomal genes (POT1, ATM and HIST1H2AA) were preferentially methylated by PGE2. Biofunctional work revealed that POT1 functions as a tumor suppressor. Finally, we demonstrated that combinatorial inhibition of COX-2 and DNMT using Celecoxib and Decitabine synergistically inhibited GC growth in vitro and in vivo. Conclusion: This study suggested that PGE2 promotes DNA methylation in GC, and that co-targeting of PGE2 and DNMT inhibits GC.


Assuntos
Ciclo-Oxigenase 2/metabolismo , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA/efeitos dos fármacos , Dinoprostona/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Animais , Ciclo-Oxigenase 2/genética , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Humanos , Camundongos , Camundongos Transgênicos , Regiões Promotoras Genéticas/genética , Regulação para Cima , DNA Metiltransferase 3B
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