| 2018 statistical data showed that gastric cancer is the third leading cause of cancer-related death worldwide,and the incidence of gastric cancer ranks fifth among all cancers.Gastric cancer is divided into two subtypes in histology: intestinal and diffuse.Intestinal gastric cancer can form a distinct tissue structure with a glandular growth pattern.In contrast,diffuse gastric cancer lacks intercellular adhesion,and unable to form obvious structures with diffuse infiltrating growth pattern.The lymphnode metastasis rate of early diffuse gastric cancer(7.3%)is higher than that of early intestinal gastric cancer(1.1%).Moreover,five-year survival rate 39.7% of intestinal gastric cancer patients,but only 18.3% of diffuse gastric cancer patients.Therefore,diffuse gastric cancer patients is prone to metastasis and poor trend for prognosis,compared with intestinal gastric cancer patients.At present,the mechanism for carcinogenesis and malignant process in diffuse gastric cancer has remained unresolved,lacking of further research.Previously,it was believed that the common genomic abnormality in sporadic diffuse gastric cancer is the mutation of CDH1 for loss of function,encoding protein E-cadherin,which is considered to be one of initial factors of diffuse gastric cancer.Approximately 33%-50% of sporadic diffuse gastric cancers patients have somatic mutations of CDH1.Yet,the mechanism of CDH1 aberrant in diffuse gastric cancer is still unclear.Thus,there is great significance for clinical diagnosis and treatment to investigate the mechanism of occurrence and development in diffuse gastric cancers.Previously,we performed microarray analysis of m RNA expression profiling on cancer and adjacent tissues of 6 patients with gastric cancer to screen gastric cancer related genes.We found that KRT17 encoding keratin 17(Keratin17,KRT17)might be involved in the occurrence and development of gastric cancer.Interestingly,whether KRT17 m RNA level analyzed by TCGA,GSE62254 database or KRT17 protein level analyzed by tissue array,KRT17 was significantly downregulated in diffuse gastric cancer compared with intestinal gastric cancer.And KRT17 is closely associated with poor prognosis in diffuse gastric cancer patients,but not intestinal gastric cancer patients.In addition,KRT17 expression is also positively correlated with CDH1 expression in gastric cancer tissues,which is essential for the initiation of diffuse gastric cancer.These results suggested that the abnormally low expression of KRT17 may play an important role in the development of diffuse gastric cancer.We used CRISPR-Cas9 gene editing technology to construct a KRT17 knockout gastric cancer cell line and observed its biological behavior.We found that KRT17 knockout could significantly down-regulate E-cadherin expression,changing the morphology of cells,promoting epithelial-mesenchymal transition(EMT),and improving the ability of stemness and migration in gastric cancer cells.In addition,KRT17 knockout could significantly promote the metastatic ability of gastric cancer cells in vivo.The above results suggested that KRT17 knockout could promote the stemness,migration and invasion ability and metastasis ability of gastric cancer cells by promoting the EMT process.Mechanically,KRT17 knockout promote the nuclear translocation of Yes-associated protein(YAP),activating YAP signaling.Further research suggested that KRT17 knockout could up-regulate the expression of YAP target genes,among which IL6(Interleukin 6,IL6)changed most significantly,suggesting that IL6 might mediate the malignant progression of diffuse gastric cancer.We further knocked down IL6 in KRT17 knockout cell line,and found that knockdown of IL6 could reverse the EMT process,and inhibited the increase of stemness and metastatic capacity in KRT17 knockout cell lines.It was shown that the phenotype caused by KRT17 knockout is mediated by the YAP pathway.Taken together,our study revealed that the reduction of KRT17 in gastric cancer cells could down-regulate the expression level of E-cadherin,promoting EMT process,increasing stemness and metastasis,thereby regulating the malignant progression of diffuse gastric cancer.This process might be caused by the induction of IL6 expression induced by the activation of YAP signaling.The results of this study indicated that the downregulation of KRT17 might be one of the most essential factors for the development of diffuse gastric cancer.The given KRT17 / YAP / IL6 axis helps us to understand the pathogenesis and the mechanism of progression and metastasis of diffuse gastric cancer,and may serve as a diffuse target for diagnosis and treatment of diffuse gastric cancer. |
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