Roles of p38[alpha] and p38[beta] mitogen-activated protein kinase isoforms in human malignant melanoma A375 cells

• Published in: International journal of molecular medicine 2019-12, Vol.44 (6), p.2123
• Main Authors: Wen, Su-Ying, Cheng, Shi-Yann, Ng, Shang-Chuan, Aneja, Ritu, Chen, Chih-Jung, Huang, Chih-Yang, Kuo, Wei-Wen
• Format: Article
• Language: English
• Subjects: Animal genetic engineering; Cancer; Cancer metastasis; Cell cycle; EDTA; Endothelial growth factors; Endothelium; Health aspects; Instrument industry (Equipment); Melanoma; Mitogens; Protein kinases; RNA; Silence; Skin; Skin cancer; Stem cells; Tumor proteins; Tumors; Vascular endothelial growth factor
• ISSN: 1107-3756
• DOI: 10.3892/ijmm.2019.4383

Skin cancer is one of the most common cancers worldwide. Melanoma accounts for ~5% of skin cancers but causes the large majority of skin cancer-related deaths. Recent discoveries have shown that the mitogen-activated protein kinase (MAPK) signaling pathway is critical for melanoma development and progression. Many oncogenic pathways that cause melanoma tumorigenesis have been identified, most of which are due to RAF/MEK/ERK (MAPK) pathway activation. However, the precise role of p38 remains unclear. Using specific short hairpin (sh) RNA to silence p38[alpha] and p38[beta], the present findings demonstrated that p38[alpha] was a crucial factor in regulating cell migration in the A375 melanoma cell line. Silencing p38[alpha] downregulated the expression of epithelial-mesenchymal transition markers, such as matrix metallopeptidase (MMP) 2, MMP9, twist family bHLH transcription factor 1, snail family transcriptional repressor 1 and vimentin, while mesenchymal-epithelial transition markers, such as E-cadherin, were upregulated. Of note, the results also demonstrated that p38[alpha] silencing impaired vascular endothelial growth factor expression, which regulates tumor angiogenesis. Furthermore, p38[alpha] knockdown inhibited cell proliferation in melanoma cells. In addition, silencing p38[alpha] induced senescence-like features, but not cell cycle arrest. Expression of the senescence markers p16, p21, p53 and [beta]-galactosidase was upregulated, and an increase in the number of senescence-associated [beta]-galactosidase-positive cells was observed in a p38[alpha] knockdown stable clone. However, no significant difference was found between control and p38[beta] stable knockdown cells. Taken together, the present results suggested that p38[alpha] knockdown impaired migration and proliferation, and increased senescence, in A375 melanoma cells. However, p38[beta] may not be involved in melanoma tumorigenesis. Therefore, targeting p38[alpha] may be a valuable approach towards inhibiting tumor growth and metastasis in patients with melanoma. Key words: p38[alpha], epithelial-mesenchymal transition, senescence, melanoma