TRIB1 Induces Macrophages To M2-like Phenotype By Inhibiting IKB-zeta In Prostate Cancer

Background and Obective:In recent years,the incidence of prostate cancer has surged.Prostate cancer progresses very slowly compared with other cancers and has a 5-year relative survival rate of nearly 100%.However,treatment for prostate cancer can be difficult once it develops or metastasizes.Macrophages play a very interesting role in tumor progression and can be polarized into two groups in the tumor microenvironment.The antitumor-forming macrophages are the Ml type,which can be induced by lipopolysaccharide(LPS)and interferon(IFN)? and participate in innate immunity and cellular immunity.The tumor-associated macrophages(TAMs)comprise the second group and are recruited by tumor cells secreting cytokines into the tumor microenvironment.They can be induced by interleukin(IL)-4 and IL-13 in vitro and mainly function to inhibit antitumor immunity and promote angiogenesis and tissue remodeling.This phenomenon may induce tumor immune escape,prompting the immune system to ignore the occurrence of tumors.The latest research shows that TRIB1 plays a key role in the formation of TAMs in tissues.TRJB1 is associated with the occurrence of acute megakaryocyte leukemia and mediates the COP1 downregulation of C/EBPa to induce acute leukemia.Another study found that the absence of TRIB1 led to a dramatic decline in the number of macrophages not only in the bone marrow,but also in the spleen,lungs and adipose tissue.So far,the mechanism by which TRIB1 expression in tumor cells regulates the infiltration and differentiation of macrophages is not clear.Our previous study found that microRNA(miR)-224 inhibited prostate cancer progression by downregulating the expression of TRIB1.In further studies,we found that the expression of TRIB1 in prostate cancer tissue samples was related to macrophage infiltration.To clarify the effect of TRIB 1 on macrophage polarization,from our analysis of RNA sequencing data,we propose that TRIB1 affects the secretion of cytokines by regulating the NF-kB pathway in prostate cancer cells,and causes monocytes to differentiate into M2 macrophages,leading to tumor immune escape and biochemical recurrence.Methods and Results:1?Analysis of tissue microarray immunohistochemical:In Prostate Cancer Tissues,the Expression of TRIB1 was Positively Correlated with the Amount of CD163+Macrophage Infiltration.2?Transplanted tumor models:Overexpression of TRIB1 in PC3 Cells Promoted Tumor Growth and Induced CD163+ Macrophage Infiltration.3?Co-cultured prostate cancer cells(PC3 or DU145)with THP-1 cells:OE-TRIB1-PC3 Can Alter Macrophage Chemotaxis and Induce Differentiation into CD163+Macrophages.4?RNA Sequencing and Analysis of the Effect of TRIB1 on Prostate Cancer Cells(PC3,DU145).5?Elisa:TRIB1 Promotes Cytokine Secretion by Reducing IKB-zeta.6?Flow cytometry:IKB-zeta Participates in the Regulation of THP-1 Macrophage Differentiation by TRIB1 in PC3 Cells.Conclusions:1?TRIB1 is highly expressed in prostate cancer tissues and is lowly expressed in prostate non-tumor tissues.It has the potential to be used as a biomarker for the identification of benign and malignant prostate tissues.2?TRIB1 was mainly expressed in the basal cells of the prostate in benign prostate tissue.TRIB1 is a potential marker for special markers of basal cells.3?TRIB1 can induce macrophage differentiation and increase the number of type ?macrophages in prostate tissue,which reveals the characteristics of prostate cancer macrophage immunity.4?TRIB1 inhibits IKB-zeta to promote secretion of CXCL2 and IL8 in prostate cancer cells and induces THP-1 polarization to be type ? THP-1.This pathway provides a potential therapeutic target for immunotherapy of prostate cancer.