BACKGROUND V-ATPases are hetero-oligomeric enzymes consisting of 13 subunits and playing key roles in ion homeostasis and signaling. Differential expression of these proton pumps has been implicated in carcinogenesis and metastasis. To elucidate putative molecular signatures underlying these phenomena, we evaluated the expression of V-ATPase genes in esophageal squamous cell carcinoma (ESCC) and extended the analysis to other cancers. METHODS Expression of all V-ATPase genes were analyzed in ESCC by a microarray data and in different types of tumors available from public databases. Expression of C isoforms was validated by qRT-PCR in paired ESCC samples. FINDINGS A differential expression pattern of V-ATPase genes was found in different tumors, with combinations in up- and down-regulation leading to an imbalance in the expression ratios of their isoforms. Particularly, a high C1 and low C2 expression pattern accurately discriminated ESCC from normal tissues. Structural modeling of C2a isoform uncovered motifs for oncogenic kinases in an additional peptide stretch, and an actin-biding domain downstream to this sequence. INTERPRETATION Altogether these data revealed that the expression ratios of subunits/isoforms could form a conformational code that controls the H+ pump regulation and interactions related to tumorigenesis. This study establishes a paradigm change by uncovering multi-cancer molecular signatures present in the V-ATPase structure, from which future studies must address the complexity of the onco-related V-ATPase assemblies as a whole, rather than targeting changes in specific subunit isoforms. FUNDING This work was supported by grants from CNPq and FAPERJ-Brazil.

中文翻译：

---

多癌V-ATPase分子标记：食管癌中亚基C亚型的独特平衡。

背景技术V-ATP酶是由13个亚基组成的杂合寡聚酶，并且在离子稳态和信号传导中起关键作用。这些质子泵的差异表达与癌变和转移有关。为了阐明这些现象的潜在分子特征，我们评估了V-ATPase基因在食管鳞状细胞癌（ESCC）中的表达，并将该分析扩展到其他癌症。方法通过芯片数据和公共数据库中不同类型的肿瘤分析ESCC中所有V-ATPase基因的表达。通过qRT-PCR在配对的ESCC样品中验证了C亚型的表达。发现在不同的肿瘤中发现了V-ATPase基因的差异表达模式，与上调和下调的组合导致其同工型的表达比例失衡。特别是，高C1和低C2的表达模式可以准确地区分ESCC和正常组织。C2a同工型的结构建模未发现其他肽段中致癌激酶的基序，以及该序列下游的肌动蛋白结合域。解释总体而言，这些数据表明，亚基/同工型的表达率可以形成一个构象密码，该密码控制H +泵的调控以及与肿瘤发生有关的相互作用。这项研究通过揭示V-ATPase结构中存在的多癌分子特征来建立范式变化，从此以后的研究必须解决整个癌相关V-ATPase装配体的复杂性，而不是针对特定亚基同工型的变化。资金这项工作得到了CNPq和巴西FAPERJ的资助。