A Literature-Derived Muscle Wasting-Related Prognostic Signature Identifies ZBTB7C as a Candidate Associated with Tumor-Related Skeletal Muscle Alterations in Esophageal Cancer

Background: Skeletal muscle wasting is a frequent systemic complication of esophageal cancer and is associated with unfavorable clinical outcomes. However, the relationships among tumor-associated molecular characteristics, patient prognosis, and skeletal muscle alterations remain incompletely understood. This study aimed to identify prognostically relevant genes from a literature-curated muscle wasting-related gene set and investigate the potential association of ZBTB7C with tumor-related skeletal muscle alterations in esophageal squamous cell carcinoma (ESCC). Methods: Transcriptomic and survival data from the complete TCGA-ESCA cohort and the independent GSE53625 cohort were analyzed using a predefined set of genes implicated in muscle wasting-related biology. Differential expression analysis, consensus clustering, Cox regression, LASSO-Cox analysis, survival analysis, functional enrichment, and immune-related analyses were performed. A six-gene prognostic signature was constructed in the TCGA cohort and externally evaluated in GSE53625. ZBTB7C was subsequently investigated using human ESCC tissues and cell lines, Zbtb7c-overexpressing AKR cells, AKR-conditioned medium-treated C2C12 myotubes, and an immunocompetent AKR/C57BL/6 syngeneic tumor model. Results: A total of 32 literature-curated muscle wasting-related genes were retained for analysis. A six-gene prognostic signature comprising ZBTB7C, DDIT3, RNF157, AMOTL1, TTLL12, and PDLIM2 was associated with overall survival, although its discriminatory performance was limited in the external validation cohort. ZBTB7C expression was reduced in ESCC tissues and cell lines, and higher expression was associated with favorable survival. Zbtb7c overexpression reduced PCNA expression in AKR tumor cells. Conditioned medium from Zbtb7c-overexpressing AKR cells attenuated MuRF-1 and Atrogin-1 expression, partially restored AKT, FOXO3A, and P70S6K phosphorylation, and increased global protein synthesis in C2C12 myotubes. In vivo, Zbtb7c overexpression suppressed tumor growth and was accompanied by preservation of gastrocnemius muscle mass, attenuation of muscle protein homeostasis-related alterations, and a smaller decline in all-limb grip strength. Conclusions: These findings identify ZBTB7C as an exploratory candidate associated with esophageal cancer prognosis and tumor-related skeletal muscle alterations. However, its muscle-related effects cannot be fully distinguished from reduced tumor burden, and further mechanistic and clinical validation is required before its potential utility as a biomarker or therapeutic target can be established.