RESUMEN
BACKGROUND: Gastric cancer is a heterogeneous malignant disease associated with environmental and genetic predisposing factors. While gastric cancer incidence and mortality fell greatly globally over the past decades, it remains the fourth cause of cancer-related death worldwide. Thus, prevention of gastric cancer is still a major strategy for improvement of gastric cancer prognosis. SUMMARY: Helicobacter pylori infection has been demonstrated to be a major risk factor for the development of gastric cancer. Unhealthy diet and lifestyle, including high-salt food, smoking and drinking, are able to induce genotypic and phenotypic transformation of gastric epithelial cells. Gene mutations (such as E-cadherin) in stomach epithelial cells are major genetic causes for gastric cancer. The eradication of H. pylori has been demonstrated to be an effective approach for primary prevention of gastric cancer. Increased intake of a diet rich in vegetables and fresh fruits as well as smoking cessation have been shown to reduce the incidence of gastric cancer. The secondary prevention strategy is to screen premalignant gastric lesions by endoscopy. Biomarker tests are also reliable methods to identify gastric precancerous lesions. Endoscopy screening is still the gold standard for diagnosis of gastric cancer. KEY MESSAGE: H. pylori infection, a diet rich in salted and/or smoked food and red meat, as well as gene mutations are major risk factors for the development of gastric cancer. PRACTICAL IMPLICATIONS: The eradication of H. pylori is a major primary preventive strategy of gastric cancer. A healthy lifestyle, including increased intake of a diet rich in fruit and vegetables, reduced intake of salted and smoked food and red meat, a reduction of alcohol intake as well as smoking cessation will be effective approaches for the prevention of gastric cancer.
RESUMEN
Survivin overexpression is associated with poor prognosis of human gastric cancer, and is a target for gastric cancer therapy. YM155 is originally identified as a specific inhibitor of survivin. In this study, we investigated the antitumor effect of YM155 on human gastric cancer. Our results showed that YM155 treatment significantly inhibited cell proliferation, reduced colony formation and induced apoptosis of gastric cancer cells in a dose-dependent manner. Accordingly, YM155 treatment significantly decreased survivin expression without affecting XIAP expression and increased the cleavage of apoptosis-associated proteins caspase 3, 7, 8, 9. YM155 significantly inhibited sphere formation of gastric cancer cells, suppressed expansion and growth of the formed spheres (cancer stem cell-like cells, CSCs) and downregulated the protein levels of ß-catenin, c-Myc, Cyclin D1 and CD44 in gastric cancer cells. YM155 infusion at 5 mg/kg/day for 7 days markedly inhibited growth of gastric cancer xenograft in a nude mouse model. Immunohistochemistry staining and Western Blot showed that YM155 treatment inhibited expression of survivin and CD44, induced apoptosis and reduced CD44+ CSCs in xenograft tumor tissues in vivo. No obvious pathological changes were observed in organs (e.g. heart, liver, lung and kidney) in YM155-treated mice. Our results demonstrated that YM155 inhibits cell proliferation, induces cell apoptosis, reduces cancer stem cell expansion, and inhibits xenograft tumor growth in gastric cancer cells. Our results elucidate a new mechanism by which YM155 inhibits gastric cancer growth by inhibition of CSCs. YM155 may be a promising agent for gastric cancer treatment.
Asunto(s)
Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Mucosa Gástrica/metabolismo , Imidazoles/farmacología , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Naftoquinonas/farmacología , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & control , Animales , Western Blotting , Femenino , Humanos , Técnicas para Inmunoenzimas , Proteínas Inhibidoras de la Apoptosis/genética , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Estómago/patología , Neoplasias Gástricas/metabolismo , Survivin , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), a XIAP-binding protein, is a tumor suppressor gene. XAF1 was silent or expressed lowly in most human malignant tumors. However, the role of XAF1 in hepatocellular carcinoma (HCC) remains unknown. In this study, we investigated the effect of XAF1 on tumor growth and angiogenesis in hepatocellular cancer cells. Our results showed that XAF1 expression was lower in HCC cell lines SMMC-7721, Hep G2 and BEL-7404 and liver cancer tissues than that in paired non-cancer liver tissues. Adenovirus-mediated XAF1 expression (Ad5/F35-XAF1) significantly inhibited cell proliferation and induced apoptosis in HCC cells in dose- and time- dependent manners. Infection of Ad5/F35-XAF1 induced cleavage of caspase -3, -8, -9 and PARP in HCC cells. Furthermore, Ad5/F35-XAF1 treatment significantly suppressed tumor growth in a xenograft model of liver cancer cells. Western Blot and immunohistochemistry staining showed that Ad5/F35-XAF1 treatment suppressed expression of vascular endothelial growth factor (VEGF), which is associated with tumor angiogenesis, in cancer cells and xenograft tumor tissues. Moreover, Ad5/F35-XAF1 treatment prolonged the survival of tumor-bearing mice. Our results demonstrate that XAF1 inhibits tumor growth by inducing apoptosis and inhibiting tumor angiogenesis. XAF1 may be a promising target for liver cancer treatment.