Abstract
BackgroundColorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood.MethodsIn CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR’s 3’-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun’s occupancy on the C17orf91 promoter.ResultsWe observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3’-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22.ConclusionsOur findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.
Highlights
Colorectal cancer (CRC) is a severe health problem worldwide
We found that miR-22 inhibits CRC cell proliferation and migration in vitro and decelerates xenografted tumour growth in vivo by targeting Hu antigen R (HuR)
High HuR expression was found to be significantly correlated with poor survival of CRC patients (Additional file 3: Figure S1b)
Summary
Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Many risk factors for CRC have been identified, including smoking, obesity, unhealthy diet, Helicobacter pylori infection, physical inactivity and precancerous lesions [3, 4] Among these various causes of CRC, the aberrant activation or upregulation of oncogenes (e.g., KRAS [5] or EGFR [6]) and loss of function or downregulation of tumour suppressors (e.g., PDCD4 [7] or TIA1 [8]) are central. HuR mainly localises to the nucleus, until the cell receives one of various stimulations that promote the translocation of HuR to the cytoplasm [14], where HuR uses three RRMs (RNA recognition motifs) to bind UTRs (untranslated regions) of downstream mRNAs at their AREs (AU-rich elements). In a nude mouse model of CRC, HuR significantly promotes xenografted tumour growth [22] These studies support the oncogene role of HuR in CRC. The underlying mechanism for the aberrant expression of HuR in CRC is poorly understood
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