RÉSUMÉ
Ample evidence have demonstrated that long noncoding RNAs small nucleolus RNA host gene 14 (SNHG14) serves as a master regulator in various cancers. However, the exact mechanism of SNHG14 in colorectal cancer (CRC) remains unknown. In the present study, we concentrate on the potential function of SNHG14 in the pathogenesis of CRC. From the quantitative reverse transcription-polymerase chain reaction results, SNHG14 was found to be downregulated in CRC tissues compared with the normal mucous samples, and its low expression was significantly correlated with poor clinical outcomes. Overexpression of SNHG14 inhibited cell growth, induced cell apoptosis, suppressed migration and invasion by inhibiting epithelial-mesenchymal transition process. Furthermore, mechanistic studies revealed that miR-92b-3p could rescue the CRC progress induced by SNHG14. Consequently, SNHG14 exhibited low expression in CRC tissues and involved in CRC progression and metastasis by competing for miR-92b-3p, and SNHG14 could be used as a valuable biomarker and therapeutic target for CRC.
Sujet(s)
Marqueurs biologiques tumoraux/génétique , Tumeurs colorectales/anatomopathologie , Régulation de l'expression des gènes tumoraux , microARN/génétique , ARN long non codant/génétique , Apoptose , Marqueurs biologiques tumoraux/métabolisme , Prolifération cellulaire , Tumeurs colorectales/génétique , Tumeurs colorectales/métabolisme , Transition épithélio-mésenchymateuse , Femelle , Humains , Métastase lymphatique , Mâle , Adulte d'âge moyen , Pronostic , Cellules cancéreuses en cultureRÉSUMÉ
BACKGROUND & AIMS: Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive. METHODS: A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies. RESULTS: Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues; this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo. CONCLUSIONS: These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction.
Sujet(s)
Carcinome hépatocellulaire , Hépatite , Tumeurs du foie , Néovascularisation pathologique , Granulocytes neutrophiles/anatomopathologie , Carcinome hépatocellulaire/vascularisation , Carcinome hépatocellulaire/immunologie , Carcinome hépatocellulaire/mortalité , Évolution de la maladie , Cellules épithéliales/immunologie , Cellules épithéliales/métabolisme , Cellules épithéliales/anatomopathologie , Fucosyltransferases/métabolisme , Hépatite/immunologie , Hépatite/mortalité , Hépatite/anatomopathologie , Humains , Interleukine-17/métabolisme , Antigènes CD15/métabolisme , Cirrhose du foie/immunologie , Cirrhose du foie/mortalité , Cirrhose du foie/anatomopathologie , Tumeurs du foie/vascularisation , Tumeurs du foie/immunologie , Tumeurs du foie/mortalité , Matrix metalloproteinase 9/métabolisme , Néovascularisation pathologique/immunologie , Néovascularisation pathologique/mortalité , Néovascularisation pathologique/anatomopathologie , Granulocytes neutrophiles/immunologie , Granulocytes neutrophiles/métabolisme , Valeur prédictive des tests , Transduction du signal/immunologie , Taux de survie , Facteur de croissance endothéliale vasculaire de type A/métabolismeRÉSUMÉ
The proinflammatory IL-17-producing CD8(+) T cells (Tc17 cells) have recently been detected in tumors, but the nature and regulation of these cells in human tumors are presently unknown. We have recently found that IL-17(+) cells are accumulated in human hepatocellular carcinomas (HCC), where they promote disease progression by fostering angiogenesis. In this study, we showed that Tc17 cells constitute a remarkable portion of IL-17-producing cells in human HCC. Although most circulating Tc17 cells were negative for IFN-gamma, >80% of Tc17 cells in HCC tissues were positive for IFN-gamma, and they were enriched predominantly in invading tumor edge. Most CD68(+) cells located in invading tumor edge exhibited an activated phenotype and, accordingly, the activated monocytes isolated from HCC tissues were significantly superior to those isolated from nontumor tissues in inducing expansion of Tc17 cells in vitro with phenotypic features similar to those isolated from tumors. Compared with IL-17(-)IFN-gamma(+)CD8(+) cells, these IFN-gamma(+)Tc17 cells have significantly higher expression of proinflammatory cytokines (IL-2, IL-22, and TNF-alpha), but reduced expression of granzyme B and perforin. Moreover, we found that tumor-activated monocytes secreted a set of key cytokines (IL-1beta, IL-6, and IL-23) to trigger the proliferation of Tc17 cells. These data reveal an intriguing mechanism in which human Tc17 cells are generated by a fine-tuned collaborative action between different types of immune cells in distinct tumor microenvironments.