Abstract
Although recent therapeutic advances based on our understanding of molecular phenomena have prolonged the survival of melanoma patients, the prognosis of melanoma remains dismal and further understanding of the underlying mechanism of melanoma progression is needed. In this study, differential expression analyses revealed that many genes, including AKT1 and CDK2, play important roles in melanoma. Functional analyses of differentially expressed genes (DEGs), obtained from the GEO (Gene Expression Omnibus) database, indicated that high proliferative and metastatic abilities are the main characteristics of melanoma and that the PI3K and MAPK pathways play essential roles in melanoma progression. Among these DEGs, major facilitator superfamily domain-containing 12 (MFSD12) was found to have significantly and specifically upregulated expression in melanoma, and elevated MFSD12 level promoted cell proliferation by promoting cell cycle progression. Mechanistically, MFSD12 upregulation was found to activate PI3K signaling, and a PI3K inhibitor reversed the increase in cell proliferation endowed by MFSD12 upregulation. Clinically, high MFSD12 expression was positively associated with shorter overall survival (OS) and disease-free survival (DFS) in melanoma patients, and MFSD12 was an independent prognostic factor for OS and DFS in melanoma patients. Therapeutically, in vivo assays further confirmed that MFSD12 interference inhibited tumor growth and lung metastasis in melanoma. In conclusion, elevated MFSD12 expression promotes melanoma cell proliferation, and MFSD12 is a valuable prognostic biomarker and promising therapeutic target in melanoma.
Highlights
These authors contributed : Chuan-Yuan Wei, Meng-Xuan Zhu, Nan-Hang LuElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, People’s Republic of ChinaLiver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai 200032, People’s Republic of ChinaMelanoma, the most lethal type of cutaneous malignancy, has increased in incidence and mortality over the past several decades due to its aggressive clinical behavior and propensity for metastasis [1]
We investigated the expression of major facilitator superfamily domain-containing 12 (MFSD12) in a tissue microarray (TMA) containing 197 melanoma tissue samples
The PPI network analysis showed that AKT1 is located at the center of the network and is connected with multiple differentially expressed genes (DEGs); other hub genes such as CDK2, Fig. 4 MFSD12 is involved in the G1-to-S phase transition of the cell cycle. a Flow cytometric analysis of the indicated cells. b Western blot analysis of MFSD12, CDK2, cyclin D1, cyclin E1, cyclin B1, and CDK1 in the indicated cells. c Immunofluorescence staining for MFSD12, CDK2, cyclin D1, and cyclin E1 in the indicated cells. d Flow cytometric analysis of the indicated cells. e Western blot analysis of MFSD12, CDK2, cyclin D1, cyclin E1, cyclin B1, and CDK1 in the indicated cells. f Immunofluorescence staining of MFSD12, CDK2, cyclin D1, and cyclin E1 in the indicated cells
Summary
The most lethal type of cutaneous malignancy, has increased in incidence and mortality over the past several decades due to its aggressive clinical behavior and propensity for metastasis [1]. Different molecular mechanisms and various biomarkers related to the progression of melanoma have been identified; for example, more than 50% of patients present with a point mutation in the BRAF isoform, which constitutively activates MAPK signaling and plays an important role in melanoma growth, cell proliferation and migration [2]. The PI3K pathway, which plays an essential role in melanoma progression, has been reported to be commonly activated in melanoma cells [3]. Despite the great number of previous studies that have attempted to reveal the molecular mechanism of melanoma progression, the underlying mechanism has not been fully elucidated.
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