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.
Comparative analysis of expression patterns of ATP6V1C1 encoding C1 subunit of V-H+-ATPase revealed that molecular alterations correlated with endometrial cancer of better prognosis were grouped with low ATP6V1C1 expression while those correlated with worse prognosis were clustered with high ATP6V1C1 expression levels. Expression patterns of C1 subunit in endometrial adenocarcinoma are associated with molecular malignancy signatures shared by histological subtypes of highest mortality rate and suggest that G3 adenocarcinoma exhibit molecular changes resembling endometrial serous carcinoma. ATP6V1C1 might serve as novel prognostic marker allowing identification of targetable pathways for high-risk endometrial cancer.
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