PO.MCB09.03 · 分子与细胞生物学
102项包含差异表达钾通道（KCN）基因的癌症研究揭示了pH敏感性，并随机性地保留了一种拟议的由K+/H+启动的H+释放策略以实现pH逆转
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
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摘要 Abstract
中文摘要
钾通道（KCN）蛋白家族（≥90个成员）具有相互作用性，并受包括癌基因在内的众多因素影响。K+可能是相对容易脱去其水合水并置换细胞膜阴离子上质子的单价阳离子（相较于Na+）。H+以H3O+形式释放用于扩散，据推测进入Grotthuss水基质以实现质子向细胞出口的快速转移，包括携带H+的乳酸转运体，从而导致更高的细胞外H+和更低的细胞内H+以促进pH逆转（Beckner ME，Cell Settling, Migration, and Stochastic Cancer Gene Expression⋯，Biomolecules：2025，15，1177，https://doi.org/10.3390/biom15081177）。102项研究（最新总数）在无意纳入KCN基因的情况下，产生的结果显示，在30种癌症类型中，74.3%的研究含有≥1个编码pH敏感蛋白的KCN差异表达基因（DEG），并以热图、火山图等形式展示。最常见的癌症为乳腺癌、肺癌和胶质母细胞瘤，分别见于16、14和12项研究，其中68.8%、71.4%和83.3%含有≥1个pH敏感的KCN DEG。发现的63个编码KCN基因包括34个编码Kv蛋白的KCN（A-I、Q、S）、11个编码KCa蛋白的KCN（M、N、T）、8个编码Kir蛋白的KCNJ，以及10个编码K2P蛋白的KCNK。还发现3个非编码KCN。在编码KCN中，40个（63.5%）为pH敏感。最频繁的KCN DEG（均为pH敏感）为KCNN4、KCNMA1、KCNN3和KCNJ16，分别见于11、9、6和6项研究。在存在KCN DEG的情况下，发现了相对完整的非KCN DEG，这些是癌细胞由内膜K+/H+交换启动的H+释放步骤所需的。有助于K+摄入的Na/K-ATP酶及其调节因子（ATP1A2、B1、B2和/或FXYD1、D2 DEG见于9.8%的研究），以及有助于H+与乳酸一起排出的LDHA DEG（见于2.9%的研究）和单羧酸转运体复合物（CA2、CA9、SLC16A3 DEG分别见于1.0%、1.0%和2.0%的研究）。此外，怀疑缺乏由牛磺酸增强的胞质H+转运（SLC16A6和SLC36A1（PAT1）牛磺酸转运体DEG各占1%），这与替代性胞质Grotthuss快速质子转移相一致。缝隙连接蛋白可能未处于增强水平（GJA1、GJB2、GJC3 DEG分别为2.0%、1.0%和1.0%）。最频繁的致癌性非KCN DEG为BCL2和TGFB1，分别见于8项（100% pH敏感）和6项（83.3% pH敏感）研究。许多相关的非KCN DEG为0%。这些随机性发现与以下机制相一致：内膜上的K+/H+交换启动胞质质子经Grotthuss快速水转移向各位点的扩散，H+与乳酸一起或单独释放，以在癌细胞中实现pH逆转（pHe大于pHi）。在不偏向KCN DEG的情况下，基因表达的恶性图景随机性地提示，改变的pH敏感K+通量可能促进K+/H+交换，以启动增强的H+外流，从而构成一部分癌症中pH逆转的基础。
查看英文原文 English abstract
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.
利益披露 Disclosure
M. E. Beckner, None.