102 Cancer studies including differentially expressed potassium channel (KCN) genes reveal pH sensitivity with stochastic preservation of a proposed K + /H + initiated H + release strategy for pH reversal

The potassium channel (KCN) family of proteins (≥90 members) is interactive and influenced by numerous factors including oncogenes. K + is the likely monovalent cation (versus Na + ) to shed its water with relative ease and replace protons on anions of cell membranes. H + is released for diffusion as H 3 O + , putatively into a Grotthuss water matrix for rapid transfer of protons to cell exits, including transporters of lactate with H + , resulting in higher extracellular H + and lower intracellular H + to aid pH reversal (Beckner ME, Cell Settling, Migration, and Stochastic Cancer Gene Expression⋯, Biomolecules: 2025, 15,1177, https://doi.org/10.3390/biom15081177). 102 studies (new total), with no intent to include KCN genes, yielded results in 30 cancer types with ≥ 1 KCN differentially expressed gene (DEG) encoding a pH sensitive protein in 74.3% of studies, shown in heat maps, volcano plots etc. The most common cancers were breast, lung, and glioblastoma in 16, 14, and 12 studies, respectively, with 68.8%, 71.4%, and 83.3% containing ≥ 1 pH sensitive KCN DEG. 63 coding KCN genes found include 34 KCN(A-I,Q,S) encoding Kv proteins, 11 KCN (M,N,T) encoding KCa proteins, 8 KCNJ encoding Kir proteins, and 10 KCNK encoding K2P proteins. 3 non-coding KCNs were found. Among coding KCNs, 40 (63.5%) are pH sensitive. The most frequent KCN DEG (all pH sensitive), KCNN4 , KCNMA1 , KCNN3 , and KCNJ16 , were in 11, 9, 6, and 6 studies, respectively. With KCN DEG present, relatively intact non-KCN DEG were found that are needed in steps of H + release from cancer cells initiated by K + /H + exchange on inner membranes. Na/K-ATPase and its regulators ( ATP1A2 , B1 , B2 and/or FXYD1 , D2 DEG in 9.8% of studies) that aid K+ intake, and for H+ exit with lactate ( LDHA DEG in 2.9% of studies) and the monocarboxylate transporter complex ( CA2 , CA9 , SLC16A3 DEG in 1.0, 1.0, and 2.0% of studies, respectively). Also, lack of enhanced cytosolic H + transport by taurine is suspected ( SLC16A6 and SLC36A1 ( PAT1 ) taurine transporter DEG, 1% each) consistent with alternative cytosolic Grotthuss rapid proton transfer. Gap junction proteins are probably not at enhanced levels ( GJA1 , GJB2 , GJC3 DEG were 2.0, 1.0, and 1.0%, respectively). The most frequent oncogenic non KCN DEG were BCL2 and TGFB1 , 8 (100% pH sensitive) and 6 (83.3% pH sensitive) studies, respectively. Many pertinent non-KCN DEG were 0%. Stochastic findings are consistent with K + /H + exchange on inner membranes initiating cytosolic proton diffusion via Grotthuss rapid water transfer to sites with release of H + along with lactate or alone to achieve pH reversal (pHe greater than pHi) in cancer cells. Without bias for KCN DEG, gene expression malignant landscapes stochastically suggest altered pH sensitive K + flux may promote K + /H + exchange to initiate enhanced H + efflux underlying pH reversal in a subset of cancers.