Mechanism Of Hepatoma Cells Regulating Chi3l1 Secretion In Lung Epithelial Cells To Promote Lung Metastasis

Hepatocellular carcinoma(HCC)is the fifth most common malignant tumor in the world and causes the third most tumor-related death every year.Invasion and metastasis are the main causes of death in HCC patients,and lung is the most common extrahepatic metastatic organ.However,the specific mechanism of lung metastasis of HCC is still unclear,and there are also lack of effective metastatic markers and treatments in clinical practice.Therefore,to study the mechanism of lung metastasis in HCC and find specific metastasis screening marker,is of great significance for optimizing the clinical treatment strategy of liver cancer.Tumor metastasis is a multi-stage process.In this process,tumor cells could promote metastasis by “cultivating” the distant metastatic organ to form “pre-metastatic niche”,which is supportive for tumor cells to colonize.lung epithelial cells act as most common stromal cells in the lung,which play an important and fundamental role in the formation of the “pre-metastatic niche” before lung metastasis.Lung epithelial cells can be activated in a variety of ways,releasing cytokines and chemokines,causing changes in the microenvironment of lung,facilitating tumor colonization,thereby promoting metastasis.However,the interaction between tumor cells and metastatic organ cells requires a certain media.Exosomes,as microvesicles carrying biological signals,play vital roles in signal transportation among cells.Most cells in human body secrete exosomes,which contain proteins,RNA,lipids,etc..Tumor cells can secrete a large number of exosomes,mediating the interaction between tumor cells and stromal cells,and promoting the formation of “pre-metastatic niche”.In addition,the expression profile of integrins on the surface of exosomes can determine organotropic metastasis.Therefore,studying the change of lung microenvironment and important molecule in the progression of liver cancer is essential for understanding and preventing lung metastasis in HCC patients.Chi3l1,a secreted glycoprotein encoded by the CHI3L1 gene,also called YKL-40,BRP39,can be secreted by a variety of different cells,such as lung epithelial cells,smooth muscle cells,macrophages,etc.,and is an important molecule involved in the pulmonary inflammatory response.Previous study found that Chi3l1 expression levels are associated with a variety of chronic inflammatory diseases in the lungs.The level of Chi3l1 is closely related to the severity of asthma and can be used as a biomarker for asthma.In addition to mediating the progression of chronic inflammatory diseases,Chi3l1 also plays an important role in the development of tumors.It has been found that a variety of malignant tumors such as breast cancer,lung cancer,prostate cancer,colorectal cancer,melanoma,glioblastoma,including HCC,have an elevated expression of Chi3l1.Moreover,in the study of breast cancer and melanoma,Chi3l1 can promote the formation of lung metastases.However,the role and mechanism of Chi3l1 in lung metastasis of HCC still need further investigated.In our study,we first found that the level of Chi3l1 in the serum of HCC patients with lung metastasis was significantly elevated in the clinical stage.The specific expression of Chi3l1 in the lung was detected by animal model of lung metastasis.Then,the experiment showed that Chi3l1 served as a pro-metastatic molecule by enhancing the migration and invasion of HCC cells,facilitating the angiogenesis and promoting the formation of lung “pre-metastatic niche” in the process.Furthermore,we discovered HCC cells can promote the secretion of Chi3l1 in lung epithelial cells by exosomes,and the promotion ability is positively relative to the metastatic potential of HCC cells.Besides,Bortezomib can reduce the formation of lung metastases by inhibiting the secretion of Chi3l1 in lung epithelial cells.