Increased splicing factor 3b subunit 6 expression is associated with poorer prognoses and later cancer stage in comprehensive pan-cancer and hepatocellular carcinoma analyses

Alternative splicing has been recognized as a key tumorigenesis process, and an essential factor is the spliceosome protein splicing factor 3b subunit 6 (SF3B6); it is up-regulated in various malignancies, but its precise function and associated underlying mechanisms, for different cancer types, has not been fully elucidated. In this study, we analyzed SF3B6 expression among 33 different cancer types, as well as its prognostic value and association with tumor immune microenvironments, mutation burden (TMB), microsatellite instability (MSI), specific gene mutations, and single-cell carcinogenesis-related processes. We also validated liver hepatocellular carcinoma (LIHC) SF3B6 expression and prognostic value via tissue microarrays and in vitro experiments involving siRNA knockdown of SF3B6. We found that SF3B6 was significantly overexpressed in 16 different cancer types, such as LIHC and diffuse large B-cell lymphoma, which had the highest mutation frequency. This was associated with poorer clinical outcomes, in terms of overall survival, disease-specific survival, progression-free interval, and higher cancer stages. Additionally, higher SF3B6 expression had varying cancer type-dependent associations with immune cell infiltration, immune checkpoint gene expression, TMB, MSI, plus up-/down-regulation of various cancer development processes, such as metastasis at the single-cell level. In LIHC, SF3B6 expression was markedly increased versus normal tissues; its silencing resulted in reduced cell proliferation and invasiveness in vitro. Multiple cancer types had higher SF3B6 expression, which was associated with poorer prognoses and later cancer stages. This study offers novel insights into the role of SF3B6 in tumorigenesis and immune evasion, suggesting its potential as a cancer immunotherapy target.