br Introduction Connexins are transmembrane

Introduction Connexins are transmembrane proteins that allow the exchange of molecules with the extracellular environment or adjacent DC260126 via channels in the plasma membrane. Intercellular communication and exchange of biologically active molecules, salts, and nutrients to the extracellular environment are important for cell survival, and aberrant expression (up- or downregulation) of transmembrane proteins is often associated with cancerous phenotypes [1]. Gap junction signaling is responsible for a significant proportion of cellular communication, with cells using gap junctions formed from two opposing hemichannels on adjacent cells to deliver and exchange small molecules, peptides, ions, endogenous nucleic acids, and other cellular metabolites to neighboring cells. Thus, aberrant gap junction expression can alter cellular metabolism and contribute to cancer development and progression [[2], [3], [4], [5]]. Gap junctions are found in all cells in the human body and are formed from proteins called connexins [6]. At least twenty-one connexin isoforms exist in humans, and each can form homomeric channels with the same connexin isoform or heteromeric hemichannels with different connexin isoforms [7]. The most abundant and extensively studied connexin is connexin 43 (Cx43), named according to its molecular weight of 43 kDa [6]. Cx43 expression patterns have been studied in various cancer types and vary depending on the cancer type and stage [3,4,8]. To fully understand how Cx43 expression affects cancer progression, however, Cx43 expression patterns and levels must be quantified and characterized in cancer tissues from patients.
Connexin structure and their role in compound transfer between cells Gap junctions are composed of two hexameric hemi-channels aligned 2–4 nm apart on neighboring cells [1]. These channels are built from proteins called connexins and have four transmembrane domains, two extracellular loops, and three intracellular domains comprising a cytoplasmic loop and the N-terminal and C-terminal domains (Fig. 1) [9]. Initially, the transfer of molecules via gap junctions was thought to be non-specific for any molecule with a molecular weight of less than 1.5 kDa [10]. However, structural studies of connexin channels, in particular Cx43, strongly indicate specificity with regard to molecular transport and exchange. This review primarily focuses on Cx43 due to its documented role in cancer progression and metastasis and because it has greater capacity to transport macromolecules than other connexin proteins. Of the hemi-channel isoforms studied in their homomeric form, it is evident that there exists some substrate preference according to size, charge, and shape. Weber et al. investigated the ability of fluorescent probes with molecular weights between 350 and 760 kDa to move through six different homomeric channels: Cx26, Cx32, Cx37, Cx40, Cx43, and Cx45 [11]. All connexins could transfer the low molecular weight dye, the mid-weight dye was transferred efficiently across all channels (Cx37 and Cx45 pairs displayed a decrease in transfer compared to the low molecular weight dye), and Cx43 could transfer the mid-weight dye more efficiently than its counterparts. When tested with the high molecular weight probe (Mw = 760 Da), Cx32 and Cx43 transferred the probe much more efficiently than the other connexins (Cx26, Cx32, Cx37, Cx40). Cx43, Cx45, Cx40, and Cx26 all had similar permeability for cationic solutes [12]. Cx40 and Cx26 had low permeability for anionic solutes, and Cx43 and Cx45 discriminated the molecules mostly by size and independent of charge [11].
Cx43 expression in cancer Aberrant Cx43 expression, both up- and downregulation, can contribute to cancer development and progression. As shown in Table 1, Cx43 expression patterns are cancer specific and can change according to cancer stage. Although there is an overall consensus that aberrant Cx43 expression correlates with tumor growth and/or metastasis, there is not always a clear correlation between Cx43 expression, cancer stage, and cancer type.