High mobility group A2 (HMGA2) promotes EMT via MAPK pathway in prostate cancer

Abstract

Studies have shown that High mobility group A2 (HMGA2), a non-histone protein, can promote epithelial-mesenchymal transition (EMT), which plays a critical role in prostate cancer progression and metastasis. Interestingly, full-length or wild-type HMGA2 and truncated (lacking the 3'UTR) HMGA2 isoforms are overexpressed in several cancers. However, there are no studies investigating the expression and differential roles of WT vs truncated HMGA2 isoforms in prostate cancer. Immunohistochemical staining of prostate tissue microarray revealed low membrane expression in normal epithelial prostate cells, and that expression increased with tumor grade as well as a switch from predominantly cytoplasmic HMGA2 in lower tumor grades, to mostly nuclear in high grade and bone metastatic tissue. LNCaP cells stably overexpressing wild-type HMGA2 displayed nuclear localization of HMGA2 and induction of EMT associated with increased Snail, Twist and vimentin expression compared to LNCaP Neo control cells, as shown by immunofluorescence and western blot analyses. This was associated with increased cell migration on collagen shown using boyden chamber assay. Conversely, LNCaP cells overexpressing truncated HMGA2 showed cytoplasmic HMGA2 expression that did not induce EMT yet displayed increased cell proliferation and migration compared to LNCaP Neo. Both wild-type and truncated HMGA2 increased levels of phospho-ERK, and interestingly, treatment with U0126, MAPK inhibitor, antagonized wild-type HMGA2-mediated EMT and cell migration, but did not affect truncated HMGA2-mediated cell proliferation or migration. Therefore, although both wild-type and truncated HMGA2 may promote prostate tumor progression, wild-type HMGA2 acts by inducing EMT via MAPK pathway.

Migration of gastric cancer is suppressed by rabies virus glycoprotein via regulating α7-nicotinic acetylcholine receptors/ERK-EMT

“…Interestingly, we found that rL-RVG reduces the 3 1 7 phosphorylation levels of MEK/ERK and rseulted in a decrease of phosphorylation 3 1 8 levels in MLA ,α7-nAChR and si-RNA pre-treated groups compared to the ACB 3 1 9 pre-treated group. Additionally, we also achieved similar results in the change of EMT may induce EMT via ERK signaling pathways [34] .In our study, after pretreating with 3 2 2 Western blot analysis of α 7-nAChR, MEK/ERK signaling pathway and 3 7 2 epithelial/mesenchymal protein marker. b.…”

Migration of gastric cancer is suppressed by recombinant Newcastle disease virus (rL-RVG) via regulating α7-nicotinic acetylcholine receptors/ERK- EMT

“…Additionally, we also achieved similar results in the change of EMT and migration of SGC cells. Hawsawi O and Henderson V suggested that HMGA2 may induce EMT via ERK signaling pathways [32]. In our study, after pretreatment with corynoxenine, we found that the expression of N-cadherin and Vimentin was down- regulated and the expression of E-cadherin was upregulated compared to non-pretreated groups.…”

HMGA Genes and Proteins in Development and Evolution

“…Interestingly, developmentally regulated EMTs share many aspects with pathological EMTs of tumors [143][144][145]. It is important to note that the HMGA2 protein plays a similar role in tumors, where it concurs to promote EMT through the direct activation of Snai1/2 and Twist and the downregulation of E-cadherin [146][147][148][149][150][151][152][153][154][155][156]. It is feasible that HMGA2 cooperates and is recruited with different transcription factors in sequential steps of the EMT genetic program, in force of its capacity to interact with so many molecular partners [23,157].…”