Molecular mechanism of therapeutic approaches for human gastric cancer stem cells

Gastric cancer(GC)is a primary cause of cancer-related mortality worldwide,and even after therapeutic gastrectomy,survival rates remain poor.The presence of gastric cancer stem cells(GCSCs)is thought to be the major reason for resistance to anticancer treatment(chemotherapy or radiotherapy),and for the development of tumor recurrence,epithelial–mesenchymal transition,and metastases.Additionally,GCSCs have the capacity for self-renewal,differentiation,and tumor initiation.They also synthesize antiapoptotic factors,demonstrate higher performance of drug efflux pumps,and display cell plasticity abilities.Moreover,the tumor microenvironment(TME;tumor niche)that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor.However,the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential.In this review,we provide up-todate information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development.This information will support improved diagnosis,novel therapeutic approaches,and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy.To date,most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents.However,when used in combination with adjuvant therapy,treatment can improve.By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC,the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy,radiotherapy,or other adjuvant treatment.     

Virtual screening of active compounds from Artemisia argyi and potential targets against gastric ulcer based on Network pharmacology

Artemisia argyi (AA) is one of the renowned herbs in China often used in the treatment of gastric ulcer (GU). Aiming to predict the active compounds and systematically investigate the mechanisms of Artemisia argyi for GU treatment, the approach of network pharmacology, molecular docking, gene ontology (GO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were adopted, respectively, in present study. A total of 13 predicted targets of the 103 compounds in Artemisia argyi were obtained. Sorted by pathogenic mechanisms of targets and structure types of compounds, it was revealed that flavonoids and sesquiterpenes had better performance than monoterpenes. The network analysis showed that Phospholipase a2 (PA21B), Sulfotransferase family cytosolic 2b member 1 (ST2B1), Nitric-oxide synthase, endothelial (NOS3), Gastrin (GAST), neutrophil collagenase (MMP-8), Leukotriene A-4 hydrolase (LKHA4), Urease maturation factor HypB (HYPB), and Periplasmic serine endoprotease DegP (HtrA) were the key targets with intensely interaction. The functional enrichment analysis indicated that AA probably produced the gastric mucosa protection effects by synergistically regulating many biological pathways, such as NF-κB signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, and Toll-like receptor signaling pathway, etc. In addition, C73 and C15 might be promising leading compounds with good molecular docking score. As a consequence, this study holistically illuminates the active constituents and mechanisms based on data analysis, which contributes to searching for leading compounds and the development of new drugs for gastric ulcer.     

KIF14 promotes tumor progression and metastasis and is an independent predictor of poor prognosis in human gastric cancer

The kinesin family member 14 (KIF14) is a potential oncogene and is involved in the metastasis of various cancers. Nevertheless, its function in gastric cancer (GC) remains poorly defined. The expression of KIF14 was examined in GC cell lines and a clinical cohort of GC specimens by qPCR, western blotting and immunohistochemistry (IHC) staining. The relationship between KIF14 expression and the clinicopathological features was analyzed. The effect of KIF14 on cell proliferation, colony formation, invasion and migration were investigated in vitro and in vivo. The expression of KIF14 was significantly increased in the GC tissues and cell lines. High KIF14 expression was associated with tumor stage, tumor-node-metastasis (TNM) stage and metastasis. KIF14 was an independent prognostic factor for the overall survival of GC, and a higher expression of KIF14 predicted a poorer survival. KIF14 silencing resulted in attenuated proliferation, invasion and migration in human gastric cancer cells, whereas KIF14 ectopic expression facilitated these biological abilities. Notably, the depressed expression of KIF14 inhibited Akt phosphorylation, while overexpressed KIF14 augmented Akt phosphorylation. Additionally, there was a significant correlation between the expression of KIF14 and p?Akt in GC tissues. Importantly, the proliferation, invasion and migration of the GC cells, which was promoted by KIF14 overexpression, was abolished by the Akt inhibitor MK-2206, while Akt overexpression greatly rescued the effects induced by KIF14 knockdown. Our findings are the first to demonstrate that KIF14 is overexpressed in GC, is correlated with poor prognosis and plays a crucial role in the progression and metastasis of GC.     

HSP90 mRNA在胃癌和大肠癌中表达的研究

目的为探讨胃癌和大肠癌细胞HSP90 mRNA表达的特点.方法利用核酸原位杂交技术,对79例胃肠癌组织进行检测.结果表明HSP90 mRNA在胃癌和大肠癌中的阳性率分别为55.56%(15/27)和69.23%(36/52).mRNA表达与病理类型、分化程度和有否淋巴结转移有相关性.结论 HSP90 mRNA在胃肠癌中有较高表达,检测HSP90 mRNA可以作为提示预后的重要临床指标.     

幽门螺杆菌相关性胃炎与胃癌胃大部切除术后患者胃体黏膜上皮不典型增生

目的研究幽门螺杆菌(Hp)感染及胃癌胃大部切除与胃体黏膜上皮不典型增生(GED)的关系。方法采用组织病理学的方法测定了20例慢性萎缩性胃炎和20例胃癌胃大部切除术后患者胃体GED情况。Hp的测定采用1min快速尿素酶法14C呼气试验法。结果(1)20例胃大部切除术后患者中,12例存在轻度～中度胃体GED,占60%;20例慢性胃炎中,7例存在轻度胃体GED,占35%。2组之间差异有显著性(P<005)。(2)在10例Hp相关性慢性胃炎中,6例存在轻度胃体GED,占60%;在10例慢性胃炎无Hp感染中,只有1例存在轻度胃体GED,占10%;2组之间差异有显著性(P<005)。(3)在10例胃大部切除术后合并Hp感染的患者中,8例存在轻度～中度胃体GED,占80%;在10例胃大部切除术后未合并Hp感染的患者中,4例存在轻度的胃体GED,占40%,2组之间差异有显著性(P<005)。结论胃大部切除术后和Hp感染患者,胃体GED发生率增加,发生恶变的发生率更高。     

Pathogenesis and host response of Helicobacter pylori

The 5th International Workshop on Pathogenesis and Host Response in Helicobacter Infections was held in Elsinore, Denmark, 4–7 July, 2002.     

选择性环氧合酶-2抑制剂联合奥曲肽诱导人胃癌细胞的凋亡

目的探讨选择性环氧合酶-2抑制剂NS-398与奥曲肽联合应用对人胃癌细胞株BGC-823生长、凋亡的影响。方法体外培养BGC-823细胞,分别用NS-398(100μmol/L)与奥曲肽(1μmol/L)单独及联合处理不同时间后,倒置显微镜观察细胞形态学变化;观察生长曲线的变化;流式细胞仪检测细胞凋亡率;实时定量(Real-time)PCR检测COX-2mRNA的表达;Western blot法检测Caspase-3蛋白表达。结果倒置显微镜下,对照组BGC-823细胞生长良好,药物处理后,细胞变小、变圆,悬浮,联合组细胞形态学改变显著强于单纯用药组;药物作用后,细胞生长受抑制,出现负增长,联合组作用明显强于单纯用药组;流式细胞仪检测表明联合用药组诱导BGC-823细胞的凋亡率明显高于单一用药组和对照组(P0.01);各处理组均使BGC-823细胞COX-2mRNA表达下调(P0.05);药物处理后细胞Caspase-3蛋白表达明显增加。结论 NS-398、奥曲肽联合可协同抑制BGC-823细胞生长、增殖,其机制可能与下调COX-2mRNA表达、诱导肿瘤细胞凋亡相关。     

Ezrin在胃癌组织中的表达及与Hp-L型感染关系的探讨

目的通过检测胃癌组织中幽门螺杆菌L(Helicobacter pyloriL-form,Hp-L)型感染以及Ezrin的表达情况,探讨Hp-L型、Ezrin在胃癌组织中的表达及临床意义。方法 (1)应用革兰染色法和免疫组织化学Elivision法检测80例胃癌组织和40例对照组织中的Hp-L型感染情况。(2)应用免疫组织化学Elivision法检测上述各组织中Ezrin蛋白的表达。(3)应用逆转录多聚酶链反应(RT-PCR)法检测30例新鲜胃癌组织及与其相对应的30例远端切缘正常组织中Ezrin mRNA的表达。结果 (1)胃癌组中革兰染色L型的检出率为80.00%(64/80)、免疫组化Hp-L型阳性率81.25%(65/80),两种方法检测的结果具有一致性(P0.05)。80例胃癌组织中Hp-L型阳性(即革兰染色L型检出阳性和免疫组化Hp-L型抗原表达同时阳性)的病例数为56例,其阳性率为70.00%;对照组中革兰染色L型检出率为22.50%(9/40),免疫组化Hp-L型阳性率40%(16/40)二者检测结果也具有一致性(P0.05)。40例对照组织中Hp-L型阳性例数为9例,其阳性率为22.50%。胃癌组与对照组的Hp-L型阳性率相比,差异具有统计学意义(P0.05);(2)胃癌组Hp-L型感染阳性率仅与胃癌的淋巴结转移有关(P0.05),而与其他临床病理因素无关;(3)RT-PCR法和免疫组织化学Elivision法显示胃癌组中Ezrin mRNA及Ezrin蛋白的表达均高于对照组(P0.05),且经统计学分析发现Ezrin表达水平与胃癌细胞的分化程度、浸润深度及淋巴结转移有关(P0.05),而与临床分期、患者的年龄及性别无关(P0.05);(4)胃癌中Hp-L型阳性组的Ezrin蛋白表达阳性率71.43%(40/56)高于Hp-L阴性组54.17%(13/24)(P0.05),且Hp-L型阳性和Ezrin蛋白阳性呈正相关(r=0.456,P0.05)。结论 Hp-L型感染阳性率和Ezrin表达阳性率在胃癌中均较高,二者可能协同促进胃癌的发生发展及浸润转移。     

HMGA1通过Wnt/β-Catenin通路被诱导并维持胃癌细胞增殖

目的探讨HMGA1通过Wnt/β-Catenin通路在胃肿瘤形成中的作用。方法应用小干扰RNA介导的基因沉默、细胞增殖分析、PCR等技术完成实验。结果 HMGA1的特异敲除明显减少细胞生长。β-Catenin或下游c-myc的损失减少HMGA1表达,而Wnt3a处理增加HMGA1和c-myc的转录。结论这些数据表明,HMGA1参与胃癌细胞形成和增殖通过Wnt/β-Catenin通路。