Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression

AIM To detect the mechanisms of Helicobacter pylori(H. pylori) infection in the invasion and metastasis of gastric cancer(GC).METHODS Specimens from 99 patients with GC were collected. The correlation among H. pylori infection, heparanase(HPA) and mitogen-activated protein kinase(MAPK) expression, which was determined by immunohistochemistry, and the clinical features of GC was analysed using SPSS 22.0. Overall survival(OS) and relapse-free survival(RFS) of GC patients were estimated by the KaplanMeier method. Independent and multiple factors of HPA and MAPK with prognosis were determined with COX proportional hazards models. HPA and MAPK expression in MKN-45 cells infected with H. pylori was analysed using Western blot. RESULTS H. pylori infection was observed in 70 of 99 patients with GC(70.7%), which was significantly higher than that in healthy controls. H. pylori infection was related to lymph metastasis and expression of HPA and MAPK(P < 0.05); HPA expression was relevant to MAPK expression(P = 0.024). HPA and MAPK expression in MKN-45 cells was significantly upregulated following H. pylori infection and peaked at 24 h and 60 min, before decreasing(P < 0.05). SB203580, an inhibitor of MAPK, significantly decreased HPA expression. HPA was related to lymph metastasis and invasive depth. HPA positive GC cases and H. pylori positive GC cases showed poorer prognosis than HPA negative cases(P < 0.05). COX models showed that the prognosis of GC was connected with HPA expression, lymph metastasis, tissue differentiation, and invasive depth. CONCLUSION H. pylori may promote the invasion and metastasis of GC by increasing HPA expression that may associate with MAPK activation, thus causing a poorer prognosis of GC.

Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression

Correction to"Liu LP,Sheng XP,Shuai TK,Zhao YX,Li B,Li YM.Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression.World J Gastroenterol 2018;24:4565-4577[PMID:30386106 DOI:10.3748/wjg.v24.i40.4565]."In this article,we have identified some of the images in Figure 2A,C,E,G,and I are identical to the images in Figures 1B,2A,3B,3E,and 3G of another paper entitled"Liu L,Zhao Y,Fan G,Shuai T,Li B,Li Y.Helicobacter pylori infection enhances heparanase leading to cell proliferation via mitogenactivated protein kinase signalling in human gastric cancer cells.",which was published by us in the Molecular Medicine Reports in December,2018[PMID:30320396 DOI:10.3892/mmr.2018.9558].The reason why we asked to replace the pictures was that when we were simultaneously preparing to submit our two different articles to the World Journal of Gastroenterology(WJG)and Molecular Medicine Reports,we uploaded the wrong pictures to the WJG,which were same as those submitted to the Molecular Medicine Reports.We apologize for this negligence and any inconvenience that this may cause.We would be grateful if you could replace the wrong pictures with the correct ones attached.

Notch2 regulates matrix metallopeptidase 9 via PI3K/AKT signaling in human gastric carcinoma cell MKN-45

AIM：To clarify the role of activated Notch2 in the invasiveness of gastric cancer.METHODS：To investigate the invasiveness of silencing Notch2 gene expression,we established a Notch2small interfering RNA（siRNA） transfected cell line using the MKN-45 gastric cancer cell line.After the successful transfection confirmed by real-time reverse transcription-polymerase chain reaction（RT-PCR） and Western blotting,migration and invasion assays were employed to evaluate the aggressiveness of the gastric cancer.RT-PCR and Western blottings were employed to confirm the down-regulation of Notch2 and to evaluate the expression of epithelial mesenchymal transition-related gene matrix metallopeptidase 9（MMP9）,Akt,p-Akt.To confirm the relationship between PI3KAkt and MMP9,the PI3K inhibitor LY294002 was used to treat MKN-45 cells.RESULTS：Notch2 expression was dramatically decreased after Notch2 siRNA transfection（100.00% ± 9.74% vs 11.61% ± 3.85%,P 〈 0.01 by qRT-PCR）.There was also a marked reduction of Notch target gene Hes1（100.00% ± 4.74% vs 61.61% ± 3.58%,P 〈 0.05） at the mRNA,indicating an inhibition of Notch signaling.Inhibition of Notch signaling was also confirmed by the marked reduction of Notch2 intracellular domain at the protein levels（100.00% ± 9.74% vs 65.61% ± 7.58%,P 〈 0.05）.Down-regulation of Notch2 by siRNA enhanced tumor cell invasion（100.00% ± 21.64% vs 162.22% ± 16.84%,P 〈 0.05） and expression of MMP9（1.56 fold,P 〈 0.05）,and activated the pro-MMP9 protein to its active form（1.48 fold,P 〈 0.05）.There was no significant difference in the protein levels of Akt between the two groups（100.00% ± 10.87% vs 96.61% ± 7.33%,P 〉 0.05）,while down-regulation of Notch2 elevated p-Akt expression（100.00% ± 9.87% vs 154.61% ± 13.10%,P 〈 0.05）.Furthermore,p-Akt and MMP9 was down-regulated in response to the inhibitor LY294002（p-Akt 100.00% ± 8.87% vs 58.27% ± 5.01%,P 〈 0.05;MMP9 100.00% ± 9.17% vs 50.03% ± 4.88%,P 〈 0.05）.CONCLUSION：Notch2 may negatively regulate cell invasion by inhibiting the PI3K-Akt signaling pathway

Targeting NUF2 suppresses gastric cancer progression through G2/M phase arrest and apoptosis induction

Background:Gastric cancer(GC),a malignant tumor with poor prognosis,is one of the leading causes of cancer-related deaths worldwide;consequently,identifying novel therapeutic targets is crucial for its corresponding treatment.NUF2,a component of the NDC80 kinetochore complex,promotes cancer progression in multiple malignancies.Therefore,this study aimed to explore the potential of NUF2 as a therapeutic target to inhibit GC progression.Methods:Clinical samples were obtained from patients who underwent radical resection of GC at Lanzhou University Second Hospital from 2016 to 2021.Cell count assays,colony formation assays,and cell-derived xenotransplantation(CDX)models were used to determine the effects of NUF2 on GC progression.Flow cytometry was used to detect the effect of NUF2 or quercetin on cell cycle progression and apoptosis.A live-cell time-lapse imaging assay was performed to determine the effect of NUF2 on the regulation of mitotic progression.Transcriptomics was used to investigate the NUF2-associated molecular mechanisms.Virtual docking and microscale thermophoresis were used to identify NUF2 inhibitors.Finally,CDX,organoid,and patient-derived xenograft(PDX)models were used to examine the efficacy of the NUF2 inhibitor in GC.Results:NUF2 expression was significantly increased in GC and was negatively correlated with prognosis.The deletion of NUF2 suppressed GC progression both in vivo and in vitro.NUF2 significantly regulated the mitogen-activated protein kinase(MAPK)pathway,promoted G2/M phase transition,and inhibited apoptosis in GC cells.Additionally,quercetin was identified as a selective NUF2 inhibitor with low toxicity that significantly suppressed tumor growth in GC cells,organoids,CDX,and PDX models.Conclusions:Collectively,NUF2-mediated G2/M phase transition and apoptosis inhibition promoted GC progression;additionally,NUF2 inhibitors exhibited potent anti-GC activity.This study provides a new strategy for targeting NUF2 to suppress GC progression in clinical settings.