ERK3 is transcriptionally upregulated by [DELA]Np63[alpha] and mediates the role of [DELA]Np63[alpha] in suppressing cell migration in non-melanoma skin cancers

Background p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. [DELA]Np63[alpha] is the main isoform of p63 and highly expressed in Non-melanoma skin cancer (NMSC). Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activat...

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Bibliographic Details
Published in:BMC cancer 2021-02, Vol.21 (1)
Main Authors: Alshammari, Eid S, Aljagthmi, Amjad A, Stacy, Andrew J, Bottomley, Mike, Shamma, H. Nicholas, Kadakia, Madhavi P, Long, Weiwen
Format: Article
Language:English
Subjects:
Cancer
Cell migration
Development and progression
Genetic aspects
Genetic transcription
Oncology, Experimental
Protein kinases
Skin cancer
Tumor proteins
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Summary:Background p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. [DELA]Np63[alpha] is the main isoform of p63 and highly expressed in Non-melanoma skin cancer (NMSC). Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose biochemical features and cellular regulation are distinct from those of conventional MAPKs such as ERK1/2. While ERK3 has been shown to be upregulated in lung cancers and head and neck cancers, in which it promotes cancer cell migration and invasion, little is known about the implication of ERK3 in NMSCs. Methods Fluorescent immunohistochemistry was performed to evaluate the expression levels of [DELA]Np63[alpha] and ERK3 in normal and NMSC specimens. Dunnett's test was performed to compare mean fluorescence intensity (MFI, indicator of expression levels) of p63 or ERK3 between normal cutaneous samples and NMSC samples. A mixed effects (ANOVA) test was used to determine the correlation between [DELA]Np63[alpha] and ERK3 expression levels (MFI). The regulation of ERK3 by [DELA]Np63[alpha] was studied by qRT-PCR, Western blot and luciferase assay. The effect of ERK3 regulation by [DELA]Np63[alpha] on cell migration was measured by performing trans-well migration assay. Results The expression level of [DELA]Np63[alpha] is upregulated in NMSCs compared to normal tissue. ERK3 level is significantly upregulated in AK and SCC in comparison to normal tissue and there is a strong positive correlation between [DELA]Np63[alpha] and ERK3 expression in normal skin and skin specimens of patients with AK, SCC or BCC. Further, we found that [DELA]Np63[alpha] positively regulates ERK3 transcript and protein levels in A431 and HaCaT skin cells, underlying the upregulation of ERK3 expression and its positive correlation with [DELA]Np63[alpha] in NMSCs. Moreover, similar to the effect of [DELA]Np63[alpha] depletion, silencing ERK3 greatly enhanced A431 cell migration. Restoration of ERK3 expression under the condition of silencing [DELA]Np63[alpha] counteracted the increase in cell migration induced by the depletion of [DELA]Np63[alpha]. Mechanistically, ERK3 inhibits the phosphorylation of Rac1 G-protein and the formation of filopodia of A431 skin SCC cells. Conclusions ERK3 is positively regulated by [DELA]Np63[alpha] and mediates the role of [DELA]Np63[alpha] in suppressing cell migration in NMSC. Keywords: [DELA]Np63[alpha], ERK3, IHC, SCC, NMSC,
ISSN:1471-2407
1471-2407
DOI:10.1186/s12885-021-07866-w