Prognostic Significance of KIF11 and KIF14 Expression in Pancreatic Adenocarcinoma

Abstract

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.

Prognostic Impact and Functional Annotations of KIF11 and KIF14 Expression in Patients with Colorectal Cancer

“…Indeed, in contrast to KIF11 protein, high KIF11 mRNA was associated with noticeably better OS and constituted an independent predictor of improved OS in the TCGA cohort. This finding contradicts the reported poor prognosis of ovarian, pancre-atic, breast or non-small cell lung cancer patients overexpressing KIF11 mRNA [20,[24][25][26]. Nevertheless, given that protein levels equate more closely with function than mRNA levels [27], it is likely that elevated KIF11 expression is functionally linked to an adverse prognosis in CRC.…”

“…This was because various staining intensities are frequently observed in clinical practice, and these may have a biological meaning. Indeed, our recent pancreatic cancer data on KIF11 has revealed that the IRS scoring system was more informative for prognosis than PS itself [ 20 ]. Importantly, in our studies, we avoided choosing arbitrary cut-off values for the interpretation of target protein expression, and therefore we adopted outcome data-derived method from the Evaluate Cutpoint software [ 21 ].…”

“…KIF14 is called an oncogenic kinesin, and most reports have shown that it is overexpressed in numerous human cancers and correlated with a poor prognosis [ 32 , 33 , 34 , 35 ]. However, there are also studies implying the tumor-suppressive function of KIF14 in some tumors [ 20 , 36 ]; thus, its precise role may be tumor and/or context-dependent. Despite its importance, as far as we are aware, the current study is the first to investigate the clinical value of KIF14 protein in CRC patients.…”

An Integrated Bioinformatics Analysis towards the Identification of Diagnostic, Prognostic, and Predictive Key Biomarkers for Urinary Bladder Cancer

“…Neural cell adhesion molecule one ( NCAM1 ) has not been extensively investigated in BCa, but there are studies that link its expression with drug resistance in acute myeloid leukemia [ 138 ], pleuropulmonary blastoma [ 139 ], and cervical intraepithelial neoplasia [ 140 ]. Kinesin family member 14 ( KIF14 ) expression levels were linked to chemosensitivity of hepatocellular carcinoma [ 141 ] and cervical cancer [ 142 ], as well as to prognosis of various cancers, such as breast [ 143 ] and pancreatic cancer [ 144 ].…”

Role of kinesin family member 14 in disease monitoring and prognosis in patients with gastrointestinal cancer

“…In terms of the role of KIF14 expression in gastrointestinal cancer, only a few studies have reported this issue. For instance, Previous studies indicated that KIF14 is positively associated with aggravating disease features and its high expression is associated with worse survival in patients with gastric cancer and pancreatic adenocarcinoma ( 16 , 17 ). Additionally, upregulation of KIF14 has also been found to be associated with the elevated tumor stage and pathological tumor grade of patients with hepatocellular carcinoma (HCC) ( 18 ).…”