Molecular Mechanism Of Tumor-associated Macrophages Polarization Induced By Renal Cancer Stem Cell Regulated By SOX17

Renal cell carcinoma is one of the top 10 malignancies and the three most common urological cancers in the world.Seventy-five percent of all renal cell carcinoma cases are diagnosed as clear cell renal cell carcinoma(cc RCC).Most patients with early stage cc RCC can be removed from surgery,20-30% of patients may develop advanced cc RCC or suffer recurrence and metastasis.Patients with advanced cc RCC,recurrence or metastasis usually choose tyrosine kinase inhibitors(TKI)as first-line agents,but there is still a risk of drug resistance when TKI drugs are used to treat patients.For patients who develop resistance,immune checkpoint inhibitors can be used as alternative agents.However,few patients achieve lasting clinical benefit from these drugs.There are many reasons for the poor prognosis of kidney cancer,and recurrence or progression after treatment is an important cause of reduced patient survival.Therefore,it is clinically important to explore the potential mechanisms of renal cancer recurrence or progression,to find new molecules for targeting mechanisms of renal cancer,and to explore novel biomarkers that are effective in predicting renal cancer prognosis for patient treatment and survival prediction.In recent years,more and more studies have shown that in many kinds of tumors,tumor stem cells play a very important role in the process of tumorigenesis and progression.Tumor stem cells(TSCs),as small undifferentiated cells in tumors,are often considered to be related to the origin of tumors.It has been shown that tumor stem cells,compared with ordinary tumor cells,maintain the characteristics of stem cells,are in an undifferentiated state,have the potential for self-renewal and multidirectional differentiation,and possess strong tumorigenicity and drug resistance.Since 2005,Florek et al.first demonstrated the existence of kidney cancer stem cells,and other studies have shown that CD133 can be used as a marker for kidney cancer stem cells,and that CD105-positive kidney cancer cells can maintain their self-renewal and drug resistance through the Notch/Myc signaling pathway.It has also been shown that inhibition of WNT and NOTCH signaling pathways in CXCR4+MET+CD44+ kidney cancer stem cells can block their self-renewal and other stemness,further inhibiting the progression of kidney cancer.Therefore,exploring the molecular mechanisms regulating the stem cell properties of kidney cancer will be important to elucidate the progression mechanism of kidney cancer,but the relevant mechanisms are not yet clear and need further study.The preliminary results of the group showed that OV6 can be used as an epithelial marker and as a marker of tumor stem cells in a variety of tumors.Considering that there is no recognized tumor stem cell marker in the field of kidney cancer,we would like to explore whether OV6 can be used as a marker for kidney cancer stem cells.SOX17(Sex-determining region Y(SRY)-box transcription factor 17),as the gene encoded in the protein,can transcribe and translate SOX family transcription factor 17,a protein consisting of 414 amino acids,is involved in processes such as human development and cell differentiation.In recent years,several studies have shown that SOX17 inhibits the progression of cervical cancer by suppressing tumor stem cells through the wnt/β-catanin pathway;meanwhile,SOX17 can act as a promoter of biliary phenotypic differentiation,which can be used as a suppressor and therapeutic target for bile duct cancer.The group’s previous study also confirmed that SOX17 can be used as an inhibitory factor and an independent prognostic indicator in kidney cancer,but whether SOX17 can regulate the relevant properties of kidney cancer stem cells and its molecular mechanism has not been reported at home and abroad.In this study,we not only focused on the tumor stem cells themselves,but also investigated the immune microenvironment of kidney cancer stem cells.In kidney cancer,it was found that the distribution of CD44-positive kidney cancer cells significantly correlated with the infiltration density of tumor-associated macrophages(TAMs),and that inhibition of TNF-α expression in macrophages inhibited the upregulation of CD44 expression in kidney cancer cells,and that NF-κB inhibitors also inhibited the effect of macrophageinduced CD44 overexpression,and how kidney cancer stem cells activate and recruit TAMs,and how the activated TAMs further increase the properties of kidney cancer stem cells,the underlying mechanisms have not been elucidated.Combining previous literature reports with the group’s previous studies,it is suggested that SOX17 may play an important role in regulating the interaction between kidney cancer stem cells and TAMs.Through in vitro experiments,database validation,cohort analysis of large patient samples,and in vivo experimental analysis,this study found that the expression level of SOX17 in kidney cancer tissues was lower than that in normal tissues.SOX17 is an important transcription factor regulating OV6-positive renal cancer cells,and overexpression/knockdown of SOX17 significantly affects the stem cell properties of OV6-positive renal cancer cells.positive renal cancer cells,leading to M2 polarization in macrophages and significantly affecting their migratory activation and secretory valueadded functions.COX regression analysis and C-index consistency index analysis revealed that combining the expression levels of OV6,SOX17,and CD163 with TNM stage increased the accuracy of predicting the prognosis of kidney cancer patients.