Role Of ZFP36L1 In The Development And Progression Of Bladder Cancer

Bladder cancer(BC)is a widely spread disease which is associated with high morbidity,mortality,and cost.About 90% of bladder cancers are Transitional cell carcinoma(TCC)in industrialized countries.The American Cancer Society’s has estimated about 81,400 new cases of bladder cancer in the year 2020,approximately about 19,300 in women and 62,100 in men.Roughly about 17,980 will die from bladder cancer(about 13,050 men and 4,930 women).In women,new bladder cancers and deaths linked to bladder cancer have been dropped down slightly in recent years.While death rates have reported being stable but incidence rates are decreasing in men.BC is the fourth most common cancer in men,but it is less common in women.The main risk factors for bladder cancer are exposures to occupational or environmental carcinogens,especially tobacco.Most patients with bladder cancers are diagnosed after macroscopic hematuria(blood in urine),and confirm diagnosis of bladder cancer is made by transurethral resection of bladder tumor(TURBT).Transurethral resection is also the first stage of treatment of BC.Non-muscle-invasive and muscle-invasive BC are the subtypes of BC.These subtypes have different molecular and pathological features.The Cancer Genome Atlas project has identified genetic drivers for BC.Better genetic understanding of bladder cancer can lead to new therapies.Previously published data have shown that ZFP36L1 is frequently muted genes in BC.ZFP36L1 belongs to ZFP36 family members which includes ZFP36,ZFP36L1,and ZFP36L2.These are CCCH-type zinc finger proteins with two tandem zinc finger(TZF)regions.These proteins can destabilize mRNA by binding to their AU rich area.ZFP36 family members are highly expressed in some normal tissues like bladder,colon,and lungs and have been previously described as a tumor suppressor that is downregulated in several tumor types.Similarly,low ZFP36L1 expression predicted poor survival rates and poor patient outcome in pancreatic cancer.In our experiments,wefound that ZFP36L1 expression was markedly reduced in bladder cancer samples as compared to matched normal tissues.Low ZFP36L1 levels are associated with cancer cell self-renewal,differentiation,invasion and cell migration abilities.We also found that ZFP36L1 impairs bladder cancer cell proliferation in vitro.By artificially increasing the expression levels of ZFP36L1 in colony formation assay,oncosphere formation assay,and transwell invasion assay showed that it inhibits the self-renewal ability and promotes the invasion ability of bladder cancer cell lines.While knockdown of ZFP36L1 promotes the self-renewal ability and inhibits the migration and invasion abilities of bladder cancer cells.mRNA-expression analysis showed that ZFP36L1 over-expression downregulated Nanog which is well known to regulate self-renewal of cancer stem cells.As ZFP36L1 is a protein that can destabilize mRNA so it has to act together with mRNA to affect the cells growth abilities.Therefore,our findings indicate that there could be a possible relation between ZFP36L1 and Nanog in bladder cancer cell migration,invasion and self-renewal ability.This relation between ZFP36L1 with Nanog could possibly affect the overall survival rate.