Prognostic implications of markers of the metabolic phenotype in human cutaneous melanoma. (18th March 2019)

• Record Type: Journal Article
• Authors: Nájera, L.; Alonso‐Juarranz, M.; Garrido, M.; Ballestín, C.; Moya, L.; Martínez‐Díaz, M.; Carrillo, R.; Juarranz, A.; Rojo, F.; Cuezva, J.M.; Rodríguez‐Peralto, J.L.
• Is Part Of: British journal of dermatology. Volume 181:Number 1(2019)
• Page Start: 114
• Page End: 127
• Publication Date: 2019-03-18
• Subjects: Dermatology -- Periodicals; Skin -- Diseases -- Periodicals; 616.5
• DOI: 10.1111/bjd.17513
• Languages: English
• ISSNs: 0007-0963

Abstract

Summary: Background: Reprogramming of energy metabolism to enhanced aerobic glycolysis has been defined as a hallmark of cancer. Objectives: To investigate the role of the mitochondrial proteins, β‐subunit of the H + ‐ATP synthase (β‐F1‐ATPase), and heat‐shock protein 60 (HSP60), and the glycolytic markers, glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) and pyruvate kinase M2 (PKM2), as well as the bioenergetic cellular (BEC) index, in melanoma progression. Materials and methods: The expression of energy metabolism proteins was assessed on a set of different melanoma cells representing the natural biological history of the disease: primary cultures of melanocytes, radial (WM35) and vertical (WM278) growth phases, and poorly (C81‐61‐PA) and highly (C8161‐HA) aggressive melanoma cells. Cohorts of 63 melanocytic naevi, 55 primary melanomas and 35 metastases were used; and 113 primary melanoma and 33 metastases were used for validation. Results: The BEC index was significantly reduced in melanoma cells and correlated with their aggressive characteristics. Overexpression of HSP60, GAPDH and PKM2 was detected in melanoma human samples compared with naevi, showing a gradient of increased expression from radial growth phase to metastatic melanoma. The BEC index was also significantly reduced in melanoma samples and correlated with worse overall and disease‐free survival; the multivariate Cox analysis showed that the BEC index (hazard ratio 0·64; 95% confidence interval 0·4–1·2) is an independent predictor for overall survival. Conclusions: A profound alteration in the mitochondrial and glycolytic proteins and in the BEC index occurs in the progression of melanoma, which correlates with worse outcome, supporting that the alteration of the metabolic phenotype is crucial in melanoma transformation. Abstract : What's already known about this topic? Aerobic glycolysis is a hallmark in the malignant phenotype. The characterization of mitochondrial and glycolytic proteins (β‐subunit of the H + ‐ATP synthase, heat‐shock protein 60, glyceraldehyde‐3‐phosphate dehydrogenase and pyruvate kinase M2), and the bioenergetic cellular (BEC) index in melanoma has not been previously reported. What does this study add? The mitochondrial and glycolytic proteins are dysregulated and the BEC index reduced in tumour cells in the malignant transformation of melanocytes. The alteration of their expression is associated with the clinical outcome in cutaneous malignant melanoma. A BEC index reduction correlates with tumour aggressiveness and worse overall and disease‐free survival in patients with melanoma. What is the translational message? The understanding of energetic dysregulation in melanoma from in vitro and in vivo models might help to predict the evolution of this tumour in patients. Linked Comment: Armstrong. Br J Dermatol 2019; 181 :15–16 . Plain language summary available online Respond to this article