Prognostic Significance of KIF11 and KIF14 Expression in Pancreatic Adenocarcinoma.

Abstract

Simple SummaryPrognostic markers for survival stratification of patients with pancreatic adenocarcinoma (PAC) are missing yet. Therefore, the primary aim of this study was to assess the expression, clinical associations, and survival implications of KIF11 and KIF14 in PACs. In addition, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. Herein, we found that the expression patterns of KIF11 and KIF14 alter significantly in PACs, at both protein and mRNA levels, and this may be harnessed for patient prognosis. KIF11 and KIF14 could be defined as positive prognostic biomarkers based on the protein-based immunohistochemistry data, while they were associated with adverse prognosis based on the transcriptomic data. We also captured a five-gene prognostic signature and the biology associated with it. The findings of the present study suggest that KIF11 or KIF14 proteins, as well as a new five-gene panel, may serve as potentially useful prognostic biomarkers for PAC.Available biomarkers for pancreatic adenocarcinoma (PAC) are inadequate to guide individual patient prognosis or therapy. Therefore, herein we aimed to verify the hypothesis that differences in the expression of KIF11 and KIF14, i.e., molecular motor proteins being primarily implicated in cell division events could account for the differences in the clinical outcome of PAC patients. In-house immunohistochemistry was used to evaluate the protein expressions of KIF11 and KIF14 in PAC, whereas RNA-seq datasets providing transcript expression data were obtained from public sources. IHC and mRNA results were correlated with clinicopathological features and overall survival (OS). Furthermore, the genes co-expressed with KIF11 or KIF14 were predicted and functionally annotated. In our series, malignant ducts displayed more intense but less abundant KIF11 staining than normal-appearing ducts. The former was also true for KIF14, whereas the prevalence of positive staining was similar in tumor and normal adjacent tissues. Based on categorical immunoreactive scores, we found KIF11 and KIF14 to be frequently downregulated or upregulated in PAC cases, respectively, and those with elevated levels of either protein, or both together, were associated with better prognosis. Specifically, we provide the first evidence that KIF11 or KIF14 proteins can robustly discriminate between patients with better and worse OS, independently of other relevant clinical risk factors. In turn, mRNA levels of KIF11 and KIF14 were markedly elevated in tumor tissues compared to normal tissues, and this coincided with adverse prognosis, even after adjusting for multiple confounders. Tumors with low predicted KIF11 or KIF14 expression were seen to have enrichment for circadian clock, whereas those with high levels were enriched for the genomic instability-related gene set. KIF11 and KIF14 were strongly correlated with one another, and CEP55, ASPM, and GAMT were identified as the main hub genes. Importantly, the combined expression of these five genes emerged as the most powerful independent prognostic indicator associated with poor survival outcome compared to classical clinicopathological factors and any marker alone. In conclusion, our study identifies novel prognostic biomarkers for PAC, which await validation.