ERK3 is transcriptionally upregulated by ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in Non-Melanoma Skin Cancers
| Autor: | Andrew J. Stacy, Mike Bottomley, H. Nicholas Shamma, Madhavi P. Kadakia, Eid S. Alshammari, Amjad Ahmed Aljagthmi, Weiwen Long |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Transcriptional Activation rac1 GTP-Binding Protein Cancer Research Skin Neoplasms RAC1 ΔNp63α ERK3 lcsh:RC254-282 Cell Line 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Cell Movement Cell Line Tumor Genetics medicine Gene silencing Humans Phosphorylation Protein kinase A Migration Mitogen-Activated Protein Kinase 6 Chemistry Kinase Tumor Suppressor Proteins Cell migration lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease SCC NMSC Gene Expression Regulation Neoplastic HaCaT 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research Skin cancer Transcription Factors Research Article IHC |
| Zdroj: | BMC Cancer BMC Cancer, Vol 21, Iss 1, Pp 1-12 (2021) |
| DOI: | 10.21203/rs.2.23512/v1 |
| Popis: | Background p63, a member of the p53 gene family, is an important regulator for epithelial tissue growth and development. ∆Np63α 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 ΔNp63α 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 ΔNp63α and ERK3 expression levels (MFI). The regulation of ERK3 by ΔNp63α was studied by qRT-PCR, Western blot and luciferase assay. The effect of ERK3 regulation by ΔNp63α on cell migration was measured by performing trans-well migration assay. Results The expression level of ∆Np63α 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 ∆Np63α and ERK3 expression in normal skin and skin specimens of patients with AK, SCC or BCC. Further, we found that ∆Np63α positively regulates ERK3 transcript and protein levels in A431 and HaCaT skin cells, underlying the upregulation of ERK3 expression and its positive correlation with ∆Np63α in NMSCs. Moreover, similar to the effect of ∆Np63α depletion, silencing ERK3 greatly enhanced A431 cell migration. Restoration of ERK3 expression under the condition of silencing ∆Np63α counteracted the increase in cell migration induced by the depletion of ∆Np63α. 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 ∆Np63α and mediates the role of ∆Np63α in suppressing cell migration in NMSC. |
| Databáze: | OpenAIRE |
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