Cytoplasmic expression of the SALL4-A isoform is associated with favorable clinicopathological features in prostate carcinoma

Abstract

Prostate cancer (PCa) is a leading cause of cancer-related mortality among men worldwide. SALL4, a stem cell-associated transcription factor, has been implicated in tumorigenesis across multiple malignancies. However, most transcriptomic studies do not distinguish between SALL4 isoforms or resolve their subcellular protein localization. This study aimed to evaluate the isoform-specific expression of SALL4-A at the protein level and to investigate its clinicopathological, diagnostic, and prognostic significance in PCa. Publicly available transcriptomic and genomic datasets including TCGA-PRAD and Gene Expression Omnibus (GEO) were analyzed as a secondary component to provide gene-level biological context for total SALL4 expression and associated molecular programs in PCa. The primary analysis evaluated SALL4-A expression using isoform-specific immunohistochemistry (IHC) in 224 prostate tissue specimens, including 152 PCa and 72 non-malignant prostate tissue specimens. The subcellular localization of SALL4-A was assessed separately and analyzed in relation to clinicopathological parameters and patient outcomes. Public-data analyses demonstrated context-dependent variation in total SALL4 transcript expression in prostate cancer and identified SALL4-associated transcriptional, chromatin-regulatory, and stemness-related molecular programs. SALL4 genomic alterations were uncommon in the analyzed public prostate cancer datasets. Because these analyses involved total SALL4 in independent cohorts and did not resolve individual isoforms or subcellular protein localization, they were interpreted as gene-level biological context rather than as direct validation of the institutional SALL4-A IHC findings. In contrast, IHC analysis demonstrated a distinct compartment-specific pattern of SALL4-A protein expression significantly elevated in tumor tissues compared with non-neoplastic tissues, whereas nuclear expression did not differ significantly. Higher cytoplasmic SALL4-A expression was significantly associated with favorable clinicopathological features, including lower Gleason scores ( p  = 0.019), absence of bladder neck invasion ( p  = 0.040), and lymph node-negative status ( p  = 0.017). No significant association between SALL4-A expression and survival outcomes was observed. Receiver operating characteristic analysis indicated moderate diagnostic performance, with an area under the curve (AUC) of 0.778, sensitivity of 87.31%, and specificity of 55.38%. These findings emphasize the importance of isoform-specific evaluation of SALL4 in prostate cancer. While transcriptomic data indicate context-dependent dysregulation of total SALL4 expression, protein-level analysis revealed a distinct and clinically relevant expression pattern for the SALL4-A isoform, particularly within the cytoplasmic compartment. Cytoplasmic SALL4-A expression is associated with favorable clinicopathological features and may serve as a potential candidate biomarker in localized PCa.