Connexins in melanoma: Potential role of Cx46 in its aggressiveness

Abstract

The skin is the largest organ in the human body, and it is constantly exposed to environmental insults, such as bacteria, viruses, air/water pollution, sunrays (Rodrigues et al., 2019). Three layers compose the skin: the epidermis, the dermis, and the hypodermis (Debeer et al., 2013). The epidermis is the outer layer of the skin, and it is the first barrier that protects the organism from external elements. Keratinocytes, melanocytes, Langerhans cells, and Merkel cells, arranged in five cellular layers, compose the epidermis. The deepest layer of the epidermis, the stratum basale, is constantly producing new cells that differentiate and migrate to the most external layer, named as stratum corneum, where they lose their nucleus and merge. In the normal skin, the most external cells detach constantly, taking around 2 weeks from birth in the Stratum basale to their loss in the Stratum corneum. The dermis is below the Stratum basale and has several functions, such as to feed the epidermis, to

GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma

“…Lack of connexins was associated with development of chemical‐ and radiation‐induced tumours, 7,8 while reintroduction of connexins was shown to decrease tumorigenic behaviours 9 . Recently, Tittarelli and coworkers identified connexin 43 (Cx43) as an important key player in melanoma development and suggested the use of compounds that selectively enhance connexin expression for melanoma therapy 12 . For example, all‐trans retinoic acid (ATRA), an analogue of vitamin A, is currently being studied extensively for its potential as a therapeutic and chemopreventive agent.…”

“…In particular, both GJB5 (gap‐junction protein, Beta 5, Cx31·1) and GJB2 (gap‐junction protein, Beta 2, Cx26) were significantly downregulated in metastases compared with vertical growth phase melanomas (VGPM). GJB2 expression in melanoma tissue has been shown to promote a metastatic cell phenotype and enhance the establishment of new tumour niches through cell‐to‐cell communication with the surrounding tissue 12 . Regarding GJB5, a recent report has shown that it acts as a key regulator of migration and invasion in lung cancer cells, 14 although no specific study on GJB5 in melanoma has been published so far.…”

“…Finally, a recent report revealed an important role for Cx43 in controlling melanoma growth, death and metastasis, emphasizing the potential use of compounds that selectively enhance connexin expression in future chemotherapy/immunotherapy protocols 11 . An even more recent review suggests that Cx46 could also have an important role in melanoma growth and early stages of metastasis, encouraging the scientific community to further investigate the role of connexins in melanoma progression and survival 12 …”

“…GJB2 expression in melanoma tissue has been shown to promote a metastatic cell phenotype and enhance the establishment of new tumour niches through cell-to-cell communication with the surrounding tissue. 12 Regarding GJB5, a recent report has shown that it acts as a key regulator of migration and invasion in lung cancer cells, 14 although no specific study on GJB5 in melanoma has been published so far. We therefore further explored the role of GJB5 in melanoma using published melanoma expression datasets, also focusing on its possible relationship with BRAF mutation.…”

Melanoma metastasis, BRAF mutation and GJB5 connexin expression: a new prognostic factor

“…Cx26, Cx43, Cx46) impacts cancer progression, and their targeting in vitro suggests their potential as therapeutic targets. 7,8 Even if the study of Scatolini et al does not further provide a functional role for GJB5 in melanoma carrying a BRAF mutation, the authors show that low expression of GJB5 inversely correlates with BRAF V600E in tissues and cultured melanoma cells. Short or long treatments with BRAF inhibitors and MAPK kinase inhibitors restored the expression of GJB5 in cells.…”