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1.
Heliyon ; 10(11): e32241, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38912446

RESUMO

Background: Gastrointestinal cancer poses a considerable global health risk, encompassing a heterogeneous spectrum of malignancies that afflict the gastrointestinal tract. It is significant to develop efficacious therapeutic agents, as they are indispensable for both the treatment and prevention of this formidable disease. Methods: In this study, we synthesized a novel thiophene derivative, designated as compound 1312. An assessment was performed to investigate its anti-proliferative activity in several cancer cell lines (GES-1, EC9706, SGC7901, and HT-29). Furthermore, we performed molecular biology techniques to investigate the inhibitory impact of compound 1312 on gastrointestinal cell lines SGC-7901 and HT-29. Results: Our findings reveal that compound 1312 exhibits significant efficacy in suppressing colony formation of cancer cells. Notably, it triggers cell cycle arrest at the G2/M phase in gastrointestinal cell lines SGC7901 and HT-29. Compound 1312 was confirmed to exert inhibitory effects on cell migration and invasion in SGC7901. Additionally, the compound elicits apoptotic cell death through the activation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP) and the caspase signaling cascade. Furthermore, in vitro experiments revealed that compound 1312 effectively suppresses both the ß-tubulin cytoskeletal network and the Wnt/ß-catenin signaling pathway. These multifaceted anti-cancer activities highlight the potential of compound 1312 as a promising therapeutic agent for the treatment of gastrointestinal malignancies. Conclusion: This study indicates the promising potential of compound 1312 as a prospective candidate agent for gastrointestinal cancer treatment. Further comprehensive investigations are needed to explore its therapeutic efficacy in greater detail.

2.
J Transl Med ; 22(1): 468, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760813

RESUMO

BACKGROUND: Gastric intestinal metaplasia (GIM) is an essential precancerous lesion. Although the reversal of GIM is challenging, it potentially brings a state-to-art strategy for gastric cancer therapeutics (GC). The lack of the appropriate in vitro model limits studies of GIM pathogenesis, which is the issue this work aims to address for further studies. METHOD: The air-liquid interface (ALI) model was adopted for the long-term culture of GIM cells in the present work. This study conducted Immunofluorescence (IF), quantitative real-time polymerase chain reaction (qRT-PCR), transcriptomic sequencing, and mucoproteomic sequencing (MS) techniques to identify the pathways for differential expressed genes (DEGs) enrichment among different groups, furthermore, to verify novel biomarkers of GIM cells. RESULT: Our study suggests that GIM-ALI model is analog to the innate GIM cells, which thus can be used for mucus collection and drug screening. We found genes MUC17, CDA, TRIM15, TBX3, FLVCR2, ONECUT2, ACY3, NMUR2, and MAL2 were highly expressed in GIM cells, while GLDN, SLC5A5, MAL, and MALAT1 showed down-regulated, which can be used as potential biomarkers for GIM cells. In parallel, these genes that highly expressed in GIM samples were mainly involved in cancer-related pathways, such as the MAPK signal pathway and oxidative phosphorylation signal pathway. CONCLUSION: The ALI model is validated for the first time for the in vitro study of GIM. GIM-ALI model is a novel in vitro model that can mimic the tissue micro-environment in GIM patients and further provide an avenue for studying the characteristics of GIM mucus. Our study identified new markers of GIM as well as pathways associated with GIM, which provides outstanding insight for exploring GIM pathogenesis and potentially other related conditions.


Assuntos
Metaplasia , Humanos , Ar , Modelos Biológicos , Mucosa Gástrica/patologia , Mucosa Gástrica/metabolismo , Estômago/patologia , Organoides/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/genética , Regulação Neoplásica da Expressão Gênica , Transcriptoma/genética , Intestinos/patologia
3.
Oncol Res ; 32(2): 283-296, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38186577

RESUMO

Nicotinamide adenine dinucleotide (NAD+) plays an essential role in cellular metabolism, mitochondrial homeostasis, inflammation, and senescence. However, the role of NAD+-regulated genes, including coding and long non-coding genes in cancer development is poorly understood. We constructed a prediction model based on the expression level of NAD+ metabolism-related genes (NMRGs). Furthermore, we validated the expression of NMRGs in gastric cancer (GC) tissues and cell lines; additionally, ß-nicotinamide mononucleotide (NMN), a precursor of NAD+, was used to treat the GC cell lines to analyze its effects on the expression level of NMRGs lncRNAs and cellular proliferation, cell cycle, apoptosis, and senescence-associated secretory phenotype (SASP). A total of 13 NMRGs-related lncRNAs were selected to construct prognostic risk signatures, and patients with high-risk scores had a poor prognosis. Some immune checkpoint genes were upregulated in the high-risk group. In addition, cell cycle, epigenetics, and senescence were significantly downregulated in the high-risk group. Notably, we found that the levels of immune cell infiltration, including CD8 T cells, CD4 naïve T cells, CD4 memory-activated T cells, B memory cells, and naïve B cells, were significantly associated with risk scores. Furthermore, the treatment of NMN showed increased proliferation of AGS and MKN45 cells. In addition, the expression of SASP factors (IL6, IL8, IL10, TGF-ß, and TNF-α) was significantly decreased after NMN treatment. We conclude that the lncRNAs associated with NAD+ metabolism can potentially be used as biomarkers for predicting clinical outcomes of GC patients.


Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Humanos , NAD , Neoplasias Gástricas/genética , Prognóstico , Biomarcadores
4.
Front Genet ; 13: 869967, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35754804

RESUMO

Gastric cancer (GC) is a highly fatal and common malignancy of the digestive system. Recent therapeutic advancements have significantly improved the clinical outcomes in GC, but due to the unavailability of suitable molecular targets, a large number of patients do not respond to the immune checkpoint inhibitors (ICI) therapy. To identify and validate potential therapeutic and prognostic targets of gastric cancer, we used the "inferCNV" R package for analyzing single-cell sequencing data (GSE112302) of GC and normal epithelial cells. First, by using LASSO, we screened genes that were highly correlated with copy number variations (CNVs). Therefrom, five gene signature (CPVL, DDC, GRTP1, ONECUT2, and PRSS21) was selected by cross-validating the prognosis and risk management with the GC RNA-seq data obtained from GEO and TCGA. Moreover, the correlation analyses between CNVs of these genes and immune cell infiltration in gastric cancer identified CPVL as a potential prognostic marker. Finally, CPVL showed high expression in gastric cancer samples and cell lines, then siRNA-mediated silencing of CPVL expression in gastric cancer cells showed significant proliferation arrest in MGC803 cells. Here, we conclude that CNVs are key regulators of the immune cells infiltration in gastric TME as well as cancer development, and CPVL could potentially be used as a prognostic and therapeutic marker in gastric cancer.

5.
Dis Markers ; 2022: 7932655, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35401882

RESUMO

Colorectal cancer (COAD) is ranked as the third most common cancer and second in terms of cancer-related deaths worldwide. Due to its poor overall survival and prognosis, the incidents of COAD are significantly increasing. Although treatment methods have greatly been improved in the last decade, it is still not good enough to have satisfactory treatment outcomes. In recent years, immunotherapy has been successful to some extent in the treatment of many cancers but still, many patients do not respond to immunotherapy. Therefore, it is essential to have a deeper understanding of the immune characteristics of the tumor microenvironment and identify meaningful immune targets. In terms of immune targets, COAD has been poorly explored; thus, in the current study, based on the immune cell infiltration score and differentially expressed genes, COAD tumors were classified into hot and cold tumors. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was used to identify hub genes, construct a prognostic model, and screen potential immune targets. In total, 12 genes (CLK3, CYSLTR2, GJA10, CYP4Z1, FAM185A, LINC00324, EEF1A1P34, EEF1B2P8, PTCSC3, MIR6780A, LINC01666, and RNU6.661P) differentially expressed between hot and cold tumors were screened out. Among them, CYSLTR2 was considered as a potential candidate gene, because it showed a significant positive correlation with immune cell infiltration and immune checkpoints (PDCD1, CD274, and CTLA4). Finally, we constructed and validated a new prognostic model for COAD showing 0.854 AUC for the ROC curve, and these results provide sufficient potential to choose CYSLTR2 as an important immune target for the prognosis of COAD.


Assuntos
Neoplasias Colorretais , Microambiente Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Humanos , Prognóstico , Curva ROC , Microambiente Tumoral/imunologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-31949467

RESUMO

OBJECTIVE: Hydroxysafflor yellow A (HSYA), an effective ingredient of the Chinese herb Carthamus tinctorius L, attenuated bleomycin-induced pulmonary fibrosis in mice. This study is to investigate the effect of HSYA on the proliferation and inflammatory level of human fetal lung fibroblasts (MRC-5 cells) induced by tumor necrosis factor-α (TNF-α) and explore the underlying mechanisms. METHODS: MRC-5 cells were treated with different concentrations of TNF-α, HSYA, or/and etanercept (ENCP, TNF-α receptor (TNFR1) antagonist, 500 ng/mL) before cell proliferation was detected. The laser confocal microscope was used to observe the role of HSYA in binding of TNF-α and its receptor. Co-immunoprecipitation was used to detect the binding of TNFR1 and TAK1-TAB2 complex. Real-time quantitative RT-PCR and western blot were used to detect the expressions of inflammation-related cytokines and proteins related with the NF-κB pathway. Luciferase reporter gene assay and chromatin coprecipitation method were used to detect the interaction between AP-1 and TGF-ß1 promoter. RESULTS: TNF-α (5 ng/mL) was used to induce inflammation and proliferation in MRC-5 cells. HSYA can partially suppress the stimulation of TNF-α on proliferation and inflammatory response of MRC-5 cells. HSYA could compete with TNF-α to bind with TNFR1 and hamper the binding of TNFR1 to TAK1-TAB2 complex. In addition, HSYA could also inhibit the activation of the NF-κB signal pathway and suppress the binding of TGF-ß1 promoter with AP-1. CONCLUSION: Evidence in this study suggested that HSYA affects TNF-α-induced proliferation and inflammatory response of MRC-5 cells through the NF-κB/AP-1 signaling pathway, which may provide theoretical basis for HSYA treatment in pulmonary fibrosis.

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