scholarly journals Normal Skin Cells Increase Aggressiveness of Cutaneous Melanoma by Promoting Epithelial-to-Mesenchymal Transition via Nodal and Wnt Activity

2021 ◽  
Vol 22 (21) ◽  
pp. 11719
Author(s):  
Gustavo Untiveros ◽  
Lindsay Dezi ◽  
Megan Gillette ◽  
Julia Sidor ◽  
Luigi Strizzi

Melanoma is a lethal form of skin cancer triggered by genetic and environmental factors. Excision of early-stage, poorly aggressive melanoma often leads to a successful outcome; however, left undiagnosed these lesions can progress to metastatic disease. This research investigates whether the exposure of poorly aggressive melanoma to certain normal skin cells can explain how non-metastatic melanoma becomes more aggressive while still confined to the skin. To this end, we used a serial co-culture approach to sequentially expose cells from two different, poorly aggressive human melanoma cell lines against normal cells of the skin beginning with normal melanocytes, then epidermal keratinocytes, and finally dermal fibroblasts. Protein extraction of melanoma cells occurred at each step of the co-culture sequence for western blot (WB) analysis. In addition, morphological and functional changes were assessed to detect differences between the serially co-cultured melanoma cells and non-co-cultured cells. Results show that the co-cultured melanoma cells assumed a more mesenchymal morphology and displayed a significant increase in proliferation and invasiveness compared to control or reference cells. WB analysis of protein from the co-cultured melanoma cells showed increased expression of Snail and decreased levels of E-cadherin suggesting that epithelial-to-mesenchymal transition (EMT) is occurring in these co-cultured cells. Additional WB analysis showed increased levels of Nodal protein and signaling and signs of increased Wnt activity in the co-cultured melanoma cells compared to reference cells. These data suggest that interaction between poorly aggressive melanoma cells with normal cells of the skin may regulate the transition from localized, poorly aggressive melanoma to invasive, metastatic disease via Nodal and/or Wnt induced EMT.

2019 ◽  
Vol 20 (3) ◽  
pp. 608 ◽  
Author(s):  
Priyanka Prasad ◽  
Andrea Vasas ◽  
Judit Hohmann ◽  
Anupam Bishayee ◽  
Dona Sinha

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative approaches, including the utility of bioactive phytochemicals to manage metastatic disease. In the present study, we investigated the potential of cirsiliol, a flavonoid isolated from Centaurea jacea L., in modulating the aggressive behavior of B16F10 metastatic melanoma cells, including EMT, and associated molecular mechanisms of action. Cirsiliol was found to be effective in restraining the colony formation and migration of fibronectin-induced B16F10 metastatic melanoma cells. Cirsiliol inhibited the activity and expression of matrix metalloproteinase-9 (MMP-9). Cirsiliol also suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (also known as Akt)/nuclear factor-κB (NF-κB) signaling pathway which, in turn, caused upregulation of E-cadherin and downregulation of N-cadherin, Snail and Twist. Based on these results, cirsiliol may be considered a promising compound against EMT in the therapeutic management of malignant melanoma.


2018 ◽  
Vol 19 (8) ◽  
pp. 2152 ◽  
Author(s):  
Tzu-Yen Yang ◽  
Mei-Li Wu ◽  
Chi-I Chang ◽  
Chih-I Liu ◽  
Te-Chih Cheng ◽  
...  

Bornyl cis-4-hydroxycinnamate, a bioactive compound isolated from Piper betle stems, has the potential for use as an anti-cancer agent. This study investigated the effects of bornyl cis-4-hydroxycinnamate on cell migration and invasion in melanoma cells. Cell migration and invasion were compared in A2058 and A375 melanoma cell lines treated with/without bornyl cis-4-hydroxycinnamate (1–6 µM). To examine whether bornyl cis-4-hydroxycinnamate has a potential anti-metastatic effect on melanoma cells, cell migration and invasion assays were performed using a Boyden chamber assay and a transwell chamber in A2058 and A375 cells. Gelatin zymography was employed to determine the enzyme activities of MMP-2 and MMP-9. Cell lysates were collected for Western blotting analysis of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitors of metalloproteinase-1/2 (TIMP-1/2), as well as key molecules in the mitogen-activated protein kinase (MAPK), focal adhesion kinase (FAK)/ phosphatidylinositide-3 kinases (PI3K)/Akt/ mammalian target of rapamycin (mTOR), growth factor receptor-bound protein 2 (GRB2) signaling pathways. Our results demonstrated that bornyl cis-4-hydroxycinnamate is a potentially useful agent that inhibits melanoma cell migration and invasion, and altered melanoma cell metastasis by reducing MMP-2 and MMP-9 expression through inhibition of the FAK/PI3K/Akt/mTOR, MAPK, and GRB2 signaling pathways. Moreover, bornyl cis-4-hydroxycinnamate inhibited the process of the epithelial-to-mesenchymal transition in A2058 and A375 melanoma cells. These findings suggested that bornyl cis-4-hydroxycinnamate has potential as a chemotherapeutic agent, and warrants further investigation for its use in the management of human melanoma.


2013 ◽  
Vol 394 (6) ◽  
pp. 773-781 ◽  
Author(s):  
Dorina Gheorgheosu ◽  
Michaela Jung ◽  
Bilge Ören ◽  
Tobias Schmid ◽  
Cristina Dehelean ◽  
...  

Abstract Betulinic acid (BA) exhibits antitumoral activity by blocking proliferation, invasion, and angiogenesis. However, the impact of BA on epithelial-to-mesenchymal transition (EMT), a hallmark of cancer metastasis induced among others by neutrophil gelatinase-associated lipocalin (NGAL), remains unknown. The present study aimed at determining the effect of BA on NGAL-induced EMT. In A375 melanoma cells, BA downregulated mesenchymal markers, increased epithelial markers, and inhibited cytoskeletal reorganization. In addition, BA limited endogenous NGAL production and further suppressed EMT induced by exogenously added NGAL and the corresponding invasive cellular phenotype. In conclusion, BA interferes with EMT-associated changes, a mechanism to antagonize invasive melanoma cells.


Author(s):  
Samer Hasan Hussein-Al-Ali ◽  
Palanisamy Arulselvan ◽  
Mohd Zobir Hussein ◽  
Sharida Fakurazi ◽  
Bullo Saifullah

Iron oxide nanoparticles (MNPs) was synthesized by coprecipitation of Fe+2and Fe+3into highly basic media, followed by coating with chitosan (CH) and polyethylene glycol (PG) to forming CH-MNPs and PG-MNPs nanoparticles, respectively. Kojic acid (Kj) drug was loaded on the CH-MNPs and PG-MNPs nanoparticles to forming Kj-CH-MNPs and Kj-PG-MNPs nanocomposites. The potential cytotoxicity of free Kj, MNPs, Kj-CH-MNPs and Kj-PG-MNPs nanocomposites was evaluated using skin cancer cells (B16-F10 melanoma cells) and normal skin cell (Human Dermal Fibroblasts murine). Kj at concentrations in the range 1.562–50 μg/mL did not affect on the viability of normal skin cell and skin cancer cells during a 72-hours incubation. The Kj-CH-MNPs and Kj-PG-MNPs nanocomposites exhibit significant cytotoxicity in skin cancer cells in a dose-dependent manner with an IC50value 47.1 and 8.4 μg/mL, respectively.


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