MiR-19a And MiR-22 Influence Colorectal Cancer Progression By Targeting Tumor Suppressor TIA1 Or Oncogene HuR,Respectively

Colorectal cancer(CRC)is one of the most prevalent malignant tumors,with high morbidity and mortality worldwide.It is composed of colon and rectal cancer.In China,CRC is currently the fifth most common cancer type and also the fifth leading cause of cancer-related death.Although advances in screening and treatment have improved the life expectancy of CRC patients in recent decades,CRC remains a major health problem all over the world.In China,although the morbidity of rectal cancer remains stable,that of colon cancer rises year by year.Much more attention should be given to the exact mechanisms contributing to the initiation and development of CRC.MicroRNAs(miRNAs)are small(19-23 nucleotides)non-coding RNA molecules that act as endogenous suppressors of gene expression by binding to the 3’-untranslated region(3’-UTR)of target mRNAs to induce translational repression or mRNA cleavage.As vital post-transcriptional regulators,miRNAs are involved in numerous physiological and pathological processes,especially in cancer.Many miRNAs are directly or indirectly correlated with cancer progression and can function as either oncomiRs or tumor suppressor miRNAs.Research on the deregulated miRNAs in cancers and finding out their target genes are of vital importance to the understanding and therapy of cancer.In this study,we focused on CRC,and studied how two important miRNAs(oncomiR miR-19a and tumor suppressor miRNA miR-22)influenced the progression of CRC by suppressing their targets(tumor suppressor TIA1 or oncogene HuR,respectively).Our study was composed by two parts.In the first part,we studied the regulatory relationship between miR-19a and TIA1,Firstly,we found that TIA1 protein levels in tumor tissues were significantly downregulated in three cancer types(CRC,lung cancer and gastric cancer)compared with the adjacent normal tissues.However,the mRNA level of TIA1 changed little.The inconsistency between TIA1 protein and mRNA levels prompted us to search for the underlining post-transcriptional regulation mechanism that controlled the downregulation of TIA1 protein.We focused on miRNAs,which represented a very important post-transcriptional regulation way.We used 3 computational algorithms to predict the possible miRNAs that could target TIA1 and found that miR-19a was an promising candidates.We then checked the level of miR-19a in the 3 cancer tissues mentioned above,and found that miR-19a was significantly upregulated in tumor tissues compared to normal adjacent tissues.What’s more,the fold change of miR-19a was highly reversely correlated with that of TIA1 protein.We then demonstrated in cells that miR-19a could inhibit TIA1 protein expression by directly binding to its 3+-UTR.We also found that the miR-19a/TIA1 regulatory relationship comprised the core section of CMYC/miR-19a/TIA1/PDCD4 regulatory axis.Next we examined the influence of miR-19a-induced-TIAl-suppression on CRC progression.We found that miR-19a could promote CRC cells proliferation and migration in vitro and CRC xenografted tumor growth in vivo by targeting TIA1.In the second part,we studied the regulatory relationship between miR-22 and HuR.We found that oncogene HuR protein level was significantly upregulated in CRC tissues,which was reversely correlated with the downregulated miR-22.HuR could promote CRC cells proliferation and migration in vitro and CRC xenografted tumor growth in vivo.By using prediction software,HuR was identified as a potential target of miR-22.Then in vitro experiment demonstrated that miR-22 could suppress HuR and thus inhibit CRC cells proliferation and migration.miR-22 could also accelerate CRC tumor growth in vivo.Interestingly,an important onco-transcription factor Jun could suppress miR-22 expression at the transcriptional level.To sum up,we identified the important functions of two regulatory axes(CMYC/miR-19a/TIA1/PDCD4 and Jun/miR-22/HuR)in CRC.Our results revealed the vital effect of miRNAs on cancer progression and the complicacy of miRNA-mRNA regulatory relationship.We wish our result could be beneficial to further elucidating the molecular mechanisms of cancer(especially CRC)and to developing new approaches for molecular therapeutics for this malignant disease.