Chapter 5 │ Page 172 human gastric cancer cells, inhibiting cancer cell proliferation through G1 phase arrest and upregulation of p21 (Cip1) and p27 (Kip1) proteins, i.e., stoichiometric cyclin-dependent kinase inhibitors [98]. Yang et al. also reported that the Cx32 protein inhibits the highly-invasive malignant phenotype of hepatocellular carcinoma (HCC) both in vitro and in vivo by negatively regulating epithelial-tomesenchymal transition (EMT), via downregulation of Snail signaling through the Wnt/ꞵ-catenin pathway [99]. EMT refers to the transformation to a more mesenchymal-like phenotypic, resulting in increased cellular motility and invasiveness. Since EMT plays a crucial role in liver cancer invasion and metastasis [100], negative regulation of EMT by Cx32 proteins is very appealing to inhibit cancer progression in HCC. Thus, Cx32 proteins can suppress cancer proliferation by a ecting the G1 phase of cell cycle, upregulation of p21 and p27 proteins, and downregulation of the EMT. Taken together, these findings support the growing concept that Cxs and GJs have several significant tumor-suppressive functions, but also highlight that the GJmediated tumor-suppressive function depends on Cx isotypes and cancer type. In fact, higher Cx expression levels are linked to a better cancer prognosis, while lower Cx expression levels correspond to a worse prognosis. This is summarized in Table 5.1 for various Cx up- and downregulations and various cancer types, based on available literature.
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