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Background:  Metallothioneins (MTs) play crucial roles in the modulation of zinc/copper homeostasis, regulation of neoplastic growth and proliferation, and protection against apoptosis. The present study attempted to visualize the prognostic landscape of MT functional isoforms and identify potential prognostic biomarkers in hepatocellular carcinoma (HCC).    Methods:  The transcriptional expression, comprehensive prognostic performances, and gene–gene interaction network of MT isoforms in HCC were evaluated  via  Oncomine, GEPIA, Kaplan–Meier plotter, and GeneMANIA databases. Characterized by good prognostic value in three external cohorts,  MT1H  was specifically selected as a potential prognostic biomarker in HCC with various clinicopathological features. Functional and pathway enrichment analyses of  MT1H  status were performed using cBioPortal, the Database for Annotation, Visualization, and Integrated Discovery (DAVID), and ssGSVA method.    Results:   MT1E/1F/1G/1H/1M/1X/2A  was greatly downregulated in HCC. Prognostic analyses elucidated the essential correlations between  MT1A/1B/1H/1X/2A/4  attenuation and poor overall survival, between  MT1B/1H/4  downregulation and worse relapse-free survival, and between  MT1A/1B/1E/1H/1M/2A/4  downregulation and diminished progression-free survival in HCC. Taken together, these results indicated the powerful prognostic value of  MT1H  among MTs in HCC. In-depth analyses suggested that  MT1H  may be more applicable to alcohol-derived HCC and involved in the downregulation of the inflammatory pathway, Jak–STAT pathway, TNF pathway, and Wnt signaling pathway.    Conclusion:  MT-specific isoforms displayed aberrant expression and varying prognostic value in HCC.  MT1H  repression in HCC was multi-dimensionally detrimental to patient outcomes. Therefore,  MT1H  was possibly associated with carcinogenesis and exploited as a novel prognostic biomarker and candidate therapeutic target for HCC.

Integrative Analysis of Metallothioneins Identifies MT1H as Candidate Prognostic Biomarker in Hepatocellular Carcinoma