Exploring Differential Connexin Expression across Melanocytic Tumor Progression Involving the Tumor Microenvironment

• Published in: Cancers Vol. 11; no. 2; p. 165
• Main Authors: Kiszner, Gergo, Balla, Peter, Wichmann, Barna, Barna, Gabor, Baghy, Kornelia, Nemeth, Istvan Balazs, Varga, Erika, Furi, Istvan, Toth, Bela, Krenacs, Tibor
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-02-2019; MDPI
• Subjects: Apoptosis; Cell growth; Cell membranes; Communication; Connexin 32; Connexin 43; Epidermis; Gap junctions; Gene expression; Isotypes; Localization; Melanocytes; Melanoma; Membrane proteins; Metastases; Metastasis; Mutation; Nevus; Tumor microenvironment; Tumors; connexin isotype expression; gap junctions; malignant melanoma; direct cell-cell communication; melanoma microenvironment; melanocytic tumor progression
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers11020165

The incidence of malignant melanoma, one of the deadliest cancers, continues to increase. Here we tested connexin (Cx) expression in primary melanocytes, melanoma cell lines and in a common nevus, dysplastic nevus, and thin, thick, and metastatic melanoma tumor progression series involving the tumor microenvironment by utilizing in silico analysis, qRT-PCR, immunocyto-/histochemistry and dye transfer tests. Primary melanocytes expressed
/Cx43,
/Cx46 and low levels of
/Cx26 and
/Cx30.2 transcripts. In silico data revealed downregulation of
/Cx43 and
/Cx26 mRNA, in addition to upregulated
/Cx32, during melanoma progression. In three melanoma cell lines, we also showed the loss of
/Cx43 and the differential expression of
/Cx32,
/Cx26,
/Cx46 and
/Cx30.2. The dominantly paranuclear localization of connexin proteins explained the ~10⁻90 times less melanoma cell coupling compared to melanocytes. In melanocytic tumor tissues, we confirmed the loss of Cx43 protein, fall of cell membrane and elevated paranuclear Cx32 with moderately increased cytoplasmic Cx26 and paranuclear Cx30.2 positivity during tumor progression. Furthermore, we found Cx43, Cx26 and Cx30 proteins upregulated in the melanoma adjacent epidermis, and Cx43 in the tumor flanking vessels. Therefore, differential connexin expression is involved in melanocytic tumor progression where varying connexin isotypes and levels reflect tumor heterogeneity-related bidirectional adaptive interactions with the microenvironment.