Down‐regulation of DAB2IP promotes colorectal cancer invasion and metastasis by translocating hnRNPK into nucleus to enhance the transcription of MMP2

Abstract

DOC-2/DAB2 interacting protein (DAB2IP) is a RasGAP protein that shows a suppressive effect on cancer progression. Our previous study showed the involvement of transcription regulation of DAB2IP in metastasis of colorectal cancer (CRC). However, the molecular mechanisms of DAB2IP in regulating the progression of CRC need to be further explored. Here, we identified heterogeneous nuclear ribonucleoprotein K (hnRNPK) and matrix metalloproteinase 2 (MMP2) as vital downstream targets of DAB2IP in CRC cells by two-dimensional fluorescence difference gel electrophoresis and cDNA microassay, respectively. Mechanistically, down-regulation of DAB2IP increased the level of hnRNPK through MAPK/ERK signaling pathway. Subsequently, translocation of hnRNPK into nucleus enhanced the transcription activity of MMP2, and therefore promoted invasion and metastasis of CRC. Down-regulation of DAB2IP correlated negatively with hnRNPK and MMP2 expressions in CRC tissues. In conclusion, our study elucidates a novel mechanism of the DAB2IP/hnRNPK/MMP2 axis in the regulation of CRC invasion and metastasis, which may be a potential therapeutic target.

DAB2IP Downregulation Enhances the Proliferation and Metastasis of Human Gastric Cancer Cells by Derepressing the ERK1/2 Pathway

“…Considering that DAB2IP plays a critical role in regulating the activation of ERK1/2 pathway in colorectal cancer [ 13 , 31 ] and activation of ERK1/2 signaling pathway contributes to tumor cell growth and metastasis [ 21 – 23 ], we asked whether DAB2IP modulates the growth and metastasis of gastric cancer cells via regulating ERK1/2 signaling pathway. In accordance with other studies [ 13 , 31 ], blockade of DAB2IP enhanced the phosphorylation of ERK1/2 in gastric cancer cells ( Figure 5(a) ) and the enhanced proliferation and migration ability induced by DAB2IP knockdown was remarkably reduced after incubation with U0126 in SGC7901 gastric cancer cells (Figures 5(c) and 5(d) ). Furthermore, EMT induced by DAB2IP knockdown was reversed after treatment with U0126 in both AGS and SGC7901 gastric cancer cells ( Figure 5(b) ).…”

Association of the single nucleotide polymorphism in chromosome 9p21 and chromosome 9q33 with coronary artery disease in Chinese population

“…On the other hand, no association between variant in rs7025486 and the incidence of CAD was observed, while the GWAS and replicating study consistently found the effects of a common variant in DAB2IP (rs7025486) on the development of CAD and other complications [ 12 , 26 , 27 ]. In cancer cells, DAB2IP, as a Ras-GTPase, exerted a suppressive effect on tumor invasion and maintained chromosomal stability [ 13 , 14 , 28 ]. However, the molecular mechanisms of DAB2IP in regulating the progression of atherosclerosis need further investigation.…”

With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment

“…As aged cells are downregulated in their expression of collagen IV [ 83 ], this may lead to more efficient BM degradation in the aged host. Additionally, in many cancers, Dab2 downregulation leads to increased transcription of the ribonucleoprotein hnRNPK, which then enhances MMP2 transcription by the metastatic cells [ 91 ]. Thus, downregulation of Dab2, as observed in OvCa metastatic cell lines, may be correlated with increased MMP2 expression.…”