Decorin Inhibits The Development Of Non-small Cell Lung Cancer By Antagonizing IGFR/AKT Pathway And Attenuating YB1 Protein Nuclear Translocation

The incidence and mortality of lung cancer ranks first in cancer in China.According to histopathology,lung cancer is divided into small-cell lung cancer(SCLC)and non-small-cell lung cancer(NSCLC).About 85 %-90 % of all lung cancer cases are diagnosed as non-small cell lung cancer.The formation of non-small cell lung cancer is a complex and multi-step development process.Therefore,it is of great significance for the treatment of non-small cell lung cancer to explore the tumor molecular mechanism that plays a key role in the development of non-small cell lung cancer and to find more tumor markers with high sensitivity and specificity.Decorin(DCN)is the main component that regulates the structure and function of extracellular matrix.It can interact with a variety of cytokines or cell membrane receptors and plays an important role in the development and metastasis of lung cancer and various tumors.However,the current research on how DCN affects the occurrence and development of non-small cell lung cancer is very limited,and the specific molecular mechanism of how DCN affects the development and metastasis is still unclear.Therefore,this study explored the main role of DCN in non-small cell lung cancer,so as to clarify the exact molecular mechanism of DCN inhibiting the occurrence and development of non-small cell lung cancer.The results are as follows:1.The expression of DCN in non-small cell lung cancer tissues and cells was significantly down-regulated:In the tissue microarray of non-small cell lung cancer patients,the intensity of DCN immunohistochemical staining was significantly weakened,indicating that the expression of DCN in non-small cell lung cancer tissues was reduced.Western blot was further used to detect the expression of DCN protein in non-small cell lung cancer tissues and non-small cell lung cancer cell lines A549,H1299,and H460.It was found that the expression level of DCN was significantly reduced compared with normal tissues / cells.It is suggested that the differential expression of DCN may be involved in the occurrence and development of non-small cell lung cancer.2.Overexpression of DCN inhibited the proliferation,migration and invasion of A549 cells in vitro:DCN was overexpressed in A549 cells.The results of CCK8 and plate clone formation experiments showed that DCN could inhibit the survival and proliferation of A549 cells.Compared with the control group,the number of cells in the DCN OE group decreased by 19.9 %,and the number of clones decreased by 47.8 %.Flow cytometry showed that the content of G1 phase cells in DCN OE group was 57.11 ±0.72 %,which was 26.6 % higher than that in control group,indicating that overexpression of DCN could block the cell cycle of A549.The results of cell scratch migration experiments showed that DCN weakened the migration and invasion ability of A549.The above conclusions were further confirmed by Western blot detection of EMT and invasion and migration-related proteins.Therefore,DCN can regulate the biological function of A549 cells and inhibit the malignant development of A549 in vitro.3.Overexpression of DCN inhibited the activation of IGFR / AKT / YB1 pathway in vitro:By overexpressing DCN in A549 cells,the changes of IGF-activated IGFR /AKT / YB1-related signaling pathway-related factors were detected.Western blot results showed that overexpression of DCN could down-regulate the expression levels of p-AKT,p-YBX1 and ZEB1 proteins.Immunofluorescence showed that overexpression of DCN attenuated the nuclear translocation of AKT downstream target YB1 protein and down-regulated the expression of EMT-related proteins,which inhibited the occurrence and development of non-small cell lung cancer.4.Overexpression of DCN inhibited the tumorigenicity of A549 cells in vivo:In vivo,the tumorigenic ability of nude mice and the expression of IGFR / AKT/ YB1 pathway proteins were detected by overexpression of DCN.The results showed that overexpression of DCN could inhibit the tumorigenic ability of nude mice.The subcutaneous tumor volume of nude mice in DCN OE group was about 34.8% of that in Control group and about 36.8% of that in Vector group.At the same time,immunohistochemistry and Western blot results showed that DCN OE group significantly reduced the expression of p-AKT and p-YB1 protein in tumor tissues.The results of in vivo and in vitro experiments were consistent.In summary,overexpression of DCN in A549 cells can down-regulate the activation level of IGF-activated IGFR / AKT pathway,and inhibit the occurrence and development of non-small cell lung cancer by reducing the nuclear translocation of AKT downstream target YB1 protein,down-regulating the expression of ZEB1 and inhibiting the EMT process of tumor cells.In this study,we first analyzed the differential expression of DCN in non-small cell lung cancer,and then studied the possible biological functions of DCN in non-small cell lung cancer from the cytological level.The exact mechanism of DCN inhibiting the occurrence and development of non-small cell lung cancer was further elucidated through in vitro and in vivo experiments,which provided a scientific and effective theoretical basis for the development of potential drug targets for non-small cell lung cancer.