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[This corrects the article on p. 1968 in vol. 14, PMID: 36310707.].
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Background: Necroptosis is a recently discovered form of cell death that plays an important role in the occurrence and development of colon adenocarcinoma (COAD). Our study aimed to construct a risk score model to predict the prognosis of patients with COAD based on necroptosis-related genes. Methods: The gene expression data of COAD and normal colon samples were obtained from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). The least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to calculate the risk score based on prognostic necroptosis-related differentially expressed genes (DEGs). Based on the risk score, patients were classified into high- and low-risk groups. Then, nomogram models were built based on the risk score and clinicopathological features. Otherwise, the model was verified in the Gene Expression Omnibus (GEO) database. Additionally, the tumor microenvironment (TME) and the level of immune infiltration were evaluated by "ESTIMATE" and single-sample gene set enrichment analysis (ssGSEA). Functional enrichment analysis was carried out to explore the potential mechanism of necroptosis in COAD. Finally, the effect of necroptosis on colon cancer cells was explored through CCK8 and transwell assays. The expression of necroptosis-related genes in colon tissues and cells treated with necroptotic inducers (TNFα) and inhibitors (NEC-1) was evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The risk score was an independent prognostic risk factor in COAD. The predictive value of the nomogram based on the risk score and clinicopathological features was superior to TNM staging. The effectiveness of the model was well validated in GSE152430. Immune and stromal scores were significantly elevated in the high-risk group. Moreover, necroptosis may influence the prognosis of COAD via influencing the cancer immune response. In in-vitro experiments, the inhibition of necroptosis can promote proliferation and invasion ability. Finally, the differential expression of necroptosis-related genes in 16 paired colon tissues and colon cancer cells was found. Conclusion: A novel necroptosis-related gene signature for forecasting the prognosis of COAD has been constructed, which possesses favorable predictive ability and offers ideas for the necroptosis-associated development of COAD.
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BACKGROUND: Interleukin (IL)-34 is a pro-inflammatory cytokine involved in tumor development. The role of IL-34 in the proliferation and epithelial-mesenchymal transition (EMT) of gastric cancer (GC) remains to be investigated. AIM: To investigate whether and how IL-34 affects the proliferation of GC cells and EMT. METHODS: Using immunohistochemical staining, the expression of IL-34 protein was detected in 60 paired GC and normal paracancerous tissues and the relationship between IL-34 and clinicopathological factors was analyzed. The expression of IL-34 mRNA and protein in normal gastric epithelial cell lines and GC was detected using quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Stable IL-34 knockdown and overexpression in AGS cell lines were established by lentiviral infection and validated by qRT-PCR and western blotting. The cholecystokinin-8 assay, clone formation assay, cell scratch assay, and transwell system were used to detect GC cell proliferation, clone formation, migration, and invasion capacity, respectively. The effects of IL-34 on the growth of GC transplant tumors were assessed using a subcutaneous transplant tumor assay in nude mice. The effects of IL-34 on the expression level of EMT-associated proteins in AGS cells were examined by western blotting. RESULTS: Expression of IL-34 protein and mRNA was higher in GC cell lines than in GES-1 cells. Compared to matched normal paraneoplastic tissues, the expression of IL-34 protein was higher in 60 GC tissues, which was correlated with tumor size, T-stage, N-stage, tumor, node and metastasis stage, and degree of differentiation. Knockdown of IL-34 expression inhibited the proliferation, clone formation, migration, and invasion of AGS cells, while overexpression of IL-34 promoted cell proliferation, clone formation, migration, and invasion. Furthermore, the reduction of IL-34 promoted the expression of E-cadherin in AGS cells but inhibited the expression of vimentin and N-cadherin. Overexpression of IL-34 inhibited E-cadherin expression but promoted expression of vimentin and N-cadherin in AGS cells. Overexpression of IL-34 promoted the growth of subcutaneous transplanted tumors in nude mice. CONCLUSION: IL-34 expression is increased in GC tissues and cell lines compared to normal gastric tissues or cell lines. In GC cells, IL-34 promoted proliferation, clone formation, migration, and invasion by regulating EMT-related protein expression cells. Interference with IL-34 may represent a novel strategy for diagnosis and targeted therapy of GC.
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BACKGROUND: Approximately 90% of new cases of noncardiac gastric cancer (GC) are related to Helicobacter pylori (H. pylori), and cytotoxin-associated gene A (CagA) is one of the main pathogenic factors. Recent studies have shown that the pharmacological effects of cryptotanshinone (CTS) can be used to treat a variety of tumors. However, the effects of CTS on H. pylori, especially CagA+ strain-induced gastric mucosal lesions, on the development of GC is unknown. AIM: To assess the role of CTS in CagA-induced proliferation and metastasis of GC cells, and determine if CagA+ H. pylori strains causes pathological changes in the gastric mucosa of mice. METHODS: The effects of CTS on the proliferation of GC cells were assessed using the Cell Counting Kit-8 (CCK-8) assay, and the abnormal growth, migration and invasion caused by CagA were detected by CCK-8 and transwell assays. After transfection with pSR-HA-CagA and treatment with CTS, proliferation and metastasis were evaluated by CCK-8 and transwell assays, respectively, and the expression of Src homology 2 (SH2) domain-containing phosphatase 2 (SHP2) and phosphorylated SHP2 (p-SHP2) was detected using western blotting in AGS cells. The enzyme-linked immunosorbent assay was used to determine the immunoglobulin G (IgG) level against CagA in patient serum. Mice were divided into four groups and administered H. pylori strains (CagA+ or CagA-) and CTS (or PBS) intragastrically, and establishment of the chronic infection model was verified using polymerase chain reaction and sequencing of isolated strains. Hematoxylin and eosin staining was used to assess mucosal erosion in the stomach and toxicity to the liver and kidney. RESULTS: CTS inhibited the growth of GC cells in dose- and time-dependent manners. Overexpression of CagA promoted the growth, migration, and invasion of GC cells. Importantly, we demonstrated that CTS significantly inhibited the CagA-induced abnormal proliferation, migration, and invasion of GC cells. Moreover, the expression of p-SHP2 protein in tumor tissue was related to the expression of IgG against CagA in the serum of GC patients. Additionally, CTS suppressed the protein expression levels of both SHP2 and p-SHP2 in GC cells. CTS suppressed CagA+ H. pylori strain-induced mucosal erosion in the stomach of mice but had no obvious effects on the CagA- H. pylori strain group. CONCLUSION: CTS inhibited CagA-induced proliferation and the epithelial-mesenchymal transition of GC cells in vitro, and CagA+ H. pylori strains caused mucosal erosions of the stomach in vivo by decreasing the protein expression of SHP2.
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Gastric cancer (GC) is one of the most common digestive malignancies globally, and the prognosis of patients with advanced tumors remains poor. Isocryptotanshinone (ICTS), isolated from Salvia miltiorrhiza, was found to inhibit the proliferation of lung and breast cancer cells. However, whether ICTS has anticancer activities against GC is unknown. In the present study, we reported that the proliferation of GC cells was inhibited by ICTS in a dose- and time-dependent manner. After treatment with ICTS, GC cells were arrested in the G1/G0 phase of cell cycle and the apoptotic cells were induced in a dose-dependent manner. Additionally, ICTS suppressed the expression of cell cycle- and apoptosis-associated proteins (e.g., Cyclin D1, phosphorylated Rb, E2F1, Mcl-1, Bcl-2, and Survivin). ICTS inhibited the phosphorylation of STAT3 in a dose-dependent manner. Down-regulated STAT3 attenuated the expression of Cyclin D1, p-Rb, and Survivin, which remarkably increased the sensitivity of ICTS in GC cells; overexpression of STAT3 restored the cell growth and proliferation and the protein expression suppressed by ICTS. ICTS also suppressed the xenograft tumor growth in BALB/c nude mice. Together, these data indicate that ICTS inhibits GC proliferation by inducing G1/G0 cell cycle arrest and apoptosis via inhibiting the STAT3 signaling pathway.