Expression Pattern of Aquaporin 1 and Aquaporin 3 in Melanocytic and Nonmelanocytic Skin Tumors

Giovana Osorio, MD, PhD; Teresa Zulueta-Dorado, MD, PhD; Patricia González-Rodríguez, PhD; José Bernabéu-Wittel, MD, PhD; Julian Conejo-Mir, MD, PhD; Reposo Ramírez-Lorca, PhD; Miriam Echevarría, PhD

Disclosures

Am J Clin Pathol. 2019;152(4):446-457. 

In This Article

Abstract and Introduction

Abstract

Objectives: Study of aquaporin 1 (AQP1) and aquaporin 3 (AQP3) expression to understand its potential role in the pathophysiology of skin cancer.

Methods: Analysis of AQP1 and AQP3 expression by immunohistochemistry of 72 skin biopsy specimens from melanocytic skin tumors, nonmelanocytic tumors, or healthy samples.

Results: AQP1 showed strong labeling in 100% of benign common melanocytic nevi. Small blood vessels, stroma, and melanophages surrounding different types of melanomas tumors also were positive. Tumoral melanocytes in atypical nevi and melanomas were negative for AQP1. AQP3 showed strong labeling in 100% of melanocytic nevi, 100% of atypical melanocytic nevi, and 100% of melanomas. In all basal cell carcinomas and squamous cell carcinomas, staining for AQP3 was positive.

Conclusions: To our knowledge, this work represents the first demonstration of AQP1/AQP3 expression in human melanocytic skin tumors. More studies are needed to understand the underlying molecular mechanisms of expression of both AQPs in melanocytic tumors and their potential as molecular therapeutic targets.

Introduction

The skin is the largest organ in the body, and in addition to forming a natural barrier, it plays several essential roles in maintaining the body's homeostasis. Thus, the skin helps to keep the fluid and electrolyte balance, modulates body temperature, helps to maintain blood volume, and possesses an important neuroreceptor and immune system that governs the relationship with our surroundings. The three most common types of skin cancer are basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The incidence of skin tumors in general has increased markedly over the past 40 years, making it a public health problem.

Aquaporin (AQP) expression has been identified in various skin structures.[1] Specifically, AQP1 has been found in the endothelium of dermal capillaries and in cultured melanocytes and fibroblasts, although, curiously, its presence in these types of cells has not been confirmed in vivo. Similarly, AQP3 has been found in keratinocytes, fibroblasts, sebaceous glands, and Langerhans cells; AQP5 in sweat glands; AQP7 in hypodermal adipocytes, AQP9 in keratinocytes and Langerhans cells; and AQP10 in keratinocytes. However, the specific roles played by many of these proteins in the skin remain uncertain.

In terms of pathology, AQP-mediated water transport has been associated with the neoangiogenesis, migration, degree of invasion, and metastatic potential of tumor cells, including the skin. Thus, AQP1 is linked to the production of tumoral neovessels, essential for the survival of cancer cells.[2] The results of animal studies have suggested a link between AQP1 and the progression of melanoma;[3,4] however, it remains to be demonstrated whether AQP1 is typically expressed in human melanomas in vivo.

There is a significant amount of evidence linking changes in AQP3 expression with tumor growth.[5] In particular, in skin cancer, AQP3 seems to play a central role. Epidermal growth factor was found to induce AQP3 expression via the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and to increase the migration and proliferation capacity of cells in two gastric carcinoma cell lines, which suggests that AQP3 may play an important role in tumor growth and dissemination.[6] Marked AQP3 expression has also been found in human squamous cell carcinoma[7] and in cell lines with epidermoid differentiation.[8] AQP3 is related to wound healing, lipid metabolism in the skin, and regulation of the proliferation and differentiation of keratinocytes, with these latter properties being attributed to its ability to transport glycerol.[9,10]

In light of the above, we hereby present an in-depth study of the expression of two AQPs—namely, AQP1 and AQP3—which are known to be closely related to cancer, in an attempt to understand their possible role in the pathology of this disease and their potential use as specific therapeutic and diagnostic targets in skin cancer.

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