## 4 Discussion
Additionally, the fact that cytoplasmic SATB1 labeling was exclusively observed in cancer cells, but not in normal cells, which retained nuclear expression in the majority of cases (95.31%), argues in favor of a potential tumor-suppressive function of SATB1 in PDAC. It is generally known that tumor suppressors possessing transcriptional functions tend to localize in the nucleus of normal cells but in the cytoplasm of cancer cells [37]. In the context of clinical utility, our study is suggestive of the opposite prognostic meaning for the cytoplasmic and nuclear SATB1 in pancreatic adenocarcinoma. However, this conclusion is hampered by the fact that, in our series, the association between high SATB1n and improved OS did not reach statistical significance. More convincing evidence is therefore required to ascertain whether the clinical impact of SATB1 indeed corresponds to its subcellular distribution in PDAC. From all this, we can more confidently conclude that our research results recommend the individual analysis of cytoplasmic and nuclear SATB1 for a more precise prognostic prediction in pancreatic adenocarcinoma. As far as we are aware, the present study is the first to distinguish the individual prognostic impact of cytoplasmic and nuclear SATB1 in PDAC. Previous studies, including our own [38], performed similar analyses in colorectal cancer [35; 39] and non-small cell lung cancer [38]. We found that in our series of PDACs, the prognostic ability of cytoplasmic SATB1 in OS analysis was even superior to nuclear SATB1. In turn, nuclear SATB1 expression was evaluated by [PERSON] et al., who demonstrated its association with adverse prognosis in pancreatobiliary-type adenocarcinomas and its ability to predict responses to adjuvant treatment in both intestinal-type and pancreatobiliary-type periampullary adenocarcinoma, including pancreatic cancer [34]. Moreover, [PERSON] et al. have shown that SATB1 expression is associated with pancreatic cancer invasion depth and tumor staging, which confirmed their in vitro results showing that SATB1 promotes pancreatic cancer proliferation and invasion [33]. Nevertheless, the authors, similar to [PERSON] et al., did not specify what type of SATB1 immunoexpression patterns they evaluated, making the results hard to compare [32; 33]. Undoubtedly interesting and complex, yet still inconsistent or contradictory picture of SATB1 emerges from pancreatic cancer studies. Therefore, SATB1's role in PDAC merits further examination in additional patient cohorts, as well as in a mechanistic context. As demonstrated by [PERSON] et al., SATB1 might promote the epithelial to mesenchymal transition by increasing the aberrant expression of \(\beta\)-catenin [40]. SATB1 has also been shown to interact with \(\beta\)-catenin and recruit it into its genomic binding sites, hence mediating Wnt/\(\beta\)-catenin signaling in T-helper type 2 cells. Additionally, in our study, SATB1 expression was found to be correlated with that of \(\beta\)-catenin, both at protein and mRNA levels [41]. Notably, in our investigation, we observed that \(\beta\)-catenin expression in PDAC was membranous and cytoplasmic but without nuclear staining. In accordance with [PERSON] et al., we found no association of cytoplasmic \(\beta\)-catenin expression with PDAC (Figure S2, Tables S4-S6); therefore, our results considered only membrane staining pattern [42]. Consistent with some previous studies, the membranous expression of \(\beta\)-catenin was significantly lower in PDAC than in adjacent normal tissue [43; 44; 45]. However, opposite findings have also been made in some other studies. Indeed, up-regulation of \(\beta\)-catenin in PDAC was presented by [PERSON] et al., [PERSON] et al. and [PERSON] et al. [42; 46; 47]. These discrepancies are most probably due to different control tissues and evaluation of different staining patterns. In contrast to our cohort, _CTNNB1_ mRNA was significantly up-regulated in PAC tissues of the TCGA cohort compared with normal pancreatic tissues.