Downregulation of DUSP9 Promotes Tumor Progression and Contributes to Poor Prognosis in Human Colorectal Cancer

Abstract

Background: Dual-specificity phosphatase 9 (DUSP9) belongs to the dual-specificity protein phosphatase subfamily. Recently, increasing attention has been paid on the role of DUSP9 in a variety of cancers. However, its functional role in tumor development is still unclear, especially in colorectal cancer (CRC). Methods: The functional role of DUSP9 in inhibiting the progression of CRC was verified using colony formation assay, wound healing assay, nude mice xenograft model, etc. RNA-seq was performed to assess the gene expression profiling in SW480 cells with DUSP9 stable knockdown and shControl cells. Bisulfite sequencing (BSE) was performed to reveal the methylation status of CpG island in the promoter of DUSP9. Results: DUSP9 was significantly downregulated in tumor tissues compared with peritumor tissues. Mechanistically, the high methylation status of CpG island in the promoter of DUSP9 may lead to the downregulation of DUSP9 in CRC. Clinically, low DUSP9 expression in CRC was closely associated with depth of invasion, metastasis (TNM) stage, and poor survival, indicating that DUSP9 may be involved in the progression of CRC. Functional study revealed that DUSP9 inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition of CRC cells both in vitro and in vivo. Transcriptome profiling studies revealed that Erk signaling was involved in the tumor progression mediated by DUSP9 silencing, which is confirmed by cell experiments and clinical tissue sample staining analysis. Conclusion: Our findings demonstrate that DUSP9 plays a critical role in the progression of CRC, and therapeutic intervention to increase the expression or activity of DUSP9 may be a potential target for CRC treatment in the future.

DUSP9, a Dual-Specificity Phosphatase with a Key Role in Cell Biology and Human Diseases

“…Finally, DUSP9 can be regulated by microRNAs (miRNAs), which are small non-coding RNAs that act as post-transcriptional regulators and which are often deregulated in pathological conditions and cancers [ 10 , 51 , 52 , 53 , 54 ]. MiR-1246 and miR-212 can target the 3′-untranslated region (UTR) of the DUSP9 transcript and reduce its expression in CRC cells and hepatoblastoma-derived HepG2 cells, respectively [ 55 , 56 ]. Moreover, Chang and collaborators previously reported a link between DUSP9 expression and miR-133b and miR-4458 in CRC [ 57 ].…”

“…Analysis of DUSP9 expression by different experimental approaches in paired CRC tissues showed the downregulation of DUSP9 mRNA and protein in CRC tissues compared to peritumoral tissues [ 56 ]. Patients with low DUSP9 transcripts had significantly shorter overall survival and recurrence-free survival than those with high protein levels.…”

“…Patients with low DUSP9 transcripts had significantly shorter overall survival and recurrence-free survival than those with high protein levels. In addition, decreased DUSP9 level was closely associated with larger tumors, deeper invasion, and advanced cancer stage, indicating that DUSP9 down-regulation is associated with tumor progression and poor prognosis in CRC [ 56 ].…”

“…At a mechanistic level, the DUSP9 promoter was hypomethylated in normal intestine compared to CRC, and the treatment of SW480 cells treated with 5-aza-dC, an inhibitor of DNA methyltransferase activity, induced DUSP9 protein level [ 56 ]. Interestingly, hypermethylation of DUSP9 promoter was also observed in many other solid tumors including bladder urothelial carcinoma, breast carcinoma, cervical squamous cell carcinoma, endocervical carcinoma, lung carcinoma, and pancreatic carcinoma.…”

“…Interestingly, hypermethylation of DUSP9 promoter was also observed in many other solid tumors including bladder urothelial carcinoma, breast carcinoma, cervical squamous cell carcinoma, endocervical carcinoma, lung carcinoma, and pancreatic carcinoma. Therefore, hypermethylation of the CpG islands near the transcription initiation site of DUSP9 promoter could in part explain DUSP9 downregulation in CRC and other cancers [ 56 ]. In addition, Qiu and collaborators showed that miRNAs also participate in DUSP9 downregulation in CRC.…”