MicroRNA-429 inhibits the migration and invasion of colon cancer cells by targeting PAK6/cofilin signaling

Abstract

MicroRNAs (miRs), a class of non-coding RNAs 18-25 nucleotides in length, can lead to mRNA degradation or inhibit protein translation by directly binding to the 3'-untranslational region (UTR) of their target mRNAs. The deregulation of miR-429 has been suggested to be involved in the development and progression of colon cancer. However, the detailed molecular mechanism involved remains to be determined. The aim of the present study was to investigate the role of miR-429 in the regulation of migration and invasion of colon cancer cells using RT-qPCR and western blotting. The results showed that the expression of miR-429 was reduced in colon cancer cell lines, when compared to a normal colon epithelial cell line. Treatment with DNA demethylation agent 5-aza-2'-deoxycytidine and histone deacetylase inhibitor phenylbutyrate (PBA), or transfection with the pre-miR-429 lentivirus plasmid led to the upregulation of miR-429 expression, as well as inhibition of migration and invasion in colon cancer cells. Investigation of the molecular mechanism showed that PAK6 was a novel target of miR-429, and the expression of PAK6 was upregulated in colon cancer tissues and cell lines, and was negatively regulated by miR-429 in colon cancer cells. Moreover, the cofilin signaling acted as a downstream effector of miR-429 in colon cancer cells. In conclusion, the results of the present study suggested that miR-429 inhibits the migration and invasion of colon cancer cells, partly at least, by mediating the expression of PAK6, as well as the activity of cofilin signaling. Therefore, miR-429 is as a potential molecular target for the treatment of colon cancer.

The role of the miR‐200 family in epithelial–mesenchymal transition in colorectal cancer: a systematic review

“…The in vitro studies and the summary of their results are described in Table 1. 12 20,21 This reduced cellular invasion and migration. Epigenetic regulation is a crucial part of determining the expression of miR-200 family.…”

“…A number of groups have identified that treatment with a demethylating agent causes subsequent upregulation of miR-200b and miR-429 in hypermethylated cell lines. 20,21 This reduced cellular invasion and migration. 21 Fessler et al demonstrated epigenetic methylation of the miR-200 family promoter regions is associated with miR-200 family repression and a mesenchymal phenotype in a group of clinical samples.…”

“…A number of studies have examined potential triggers for the switch to an epithelial or mesenchymal phenotype. 21 Fessler et al demonstrated epigenetic methylation of the miR-200 family promoter regions is associated with miR-200 family repression and a mesenchymal phenotype in a group of clinical samples. Methylation of the miR-200 family promoter regions led to repression of microRNA expression and subsequent mesenchymal marker expression (vimentin) in a number of CRC cell lines.…”

“…12,21 In oxaliplatin-resistant SW620 cells, which display mesenchymal features, treatment with a demethylating agent resulted in the restoration of expression of miR-200c and miR-141 as well as the epithelial marker, E-cadherin. Chemotherapeutic drug resistance is an important component in the treatment of CRC.…”

Structure, biochemistry, and biology of PAK kinases

“…PAK6 may also be involved in stress-signaling as it is stimulated by p38-MAP kinase (Kaur et al, 2005). Expression of PAK6 is targeted by miR-328 and miR-23a in prostate cancer cells (Liu et al, 2015; Cai et al, 2015), and by miR-429 in colon cancer cells (Tian et al, 2015). PAK6 interacts with the cell junction protein IQGAP1 in a kinase activity-dependent manner and regulates the dissociation of cell-cell junctions in growth factor-stimulated cells (Fram et al, 2014; Morse et al, 2016).…”