Identifying Mitotic Kinesins as Potential Prognostic Biomarkers in Ovarian Cancer Using Bioinformatic Analyses

Abstract

Ovarian cancer (OC) is characterized by late-stage presentation, chemoresistance, and poor survival. Evaluating the prognosis of OC patients via effective biomarkers is essential to manage OC progression and to improve survival; however, it has been barely established. Here, we intend to identify differentially expressed genes (DEGs) as potential prognostic biomarkers of OC via bioinformatic analyses. Initially, a total of thirteen DEGs were extracted from different public databases as candidates. The expression of KIF20A, one of the DEGs, was correlated with a worse outcome of OC patients. The functional correlation of the DEGs with mitosis and the prognostic value of KIF20A imply a high correlation between mitotic kinesins (KIFs) and OC development. Finally, we found that KIF20A, together with the other nine mitotic KIFs (4A, 11, 14, 15, 18A, 18B, 23, C1, and2C) were upregulated and activated in OC tissues. Among the ten, seven overexpressed mitotic KIFs (11, 14, 18B, 20A, 23, and C1) were correlated with unfavorable clinical prognosis. Moreover, KIF20A and KIF23 overexpression was associated with worse prognosis in OC patients treated with platinum/taxol chemotherapy, while OCs overexpressing mitotic KIFs (11, 15, 18B, and C1) were resistant to MAPK pathway inhibitors. In conclusion, worse outcomes of OC patients were correlated with overexpression of several mitotic KIFs, which may serve both as prognostic biomarkers and therapeutic targets for OC.

Keywords: bioinformatic analyses; mitotic kinesins; ovarian cancer; prognostic biomarkers; therapeutic targets.

Figure 1

Identification and functional characterization of DEGs in OC. (A) Four datasets (FANTOM5, HPA, GTEx, and Illumina Body Map) were used to identify silenced genes in normal ovarian tissues, and the 335 overlap genes were marked by yellow in the middle; (B) 335 silenced genes from normal ovarian tissues (left) and 6164 up-regulated genes in OC tissues from TCGA-OV dataset (right); the 13 overlap genes were marked by yellow in the middle. These 13 common genes (DEGs) are silenced in normal ovarian tissues but up-regulated in OC tissues; (C) scatter plot of enriched GO pathway statistics. Rich factor is the ratio of the DEGs number to the total gene numbers in a certain pathway. The color and size of the dots represent the range of p-value (hypergeometric test and Benjamini–Hochberg methods) and the number of DEGs mapped to the indicated pathways. Top 10 enriched pathways are showed in the figure.

Figure 2

Prognostic values of 13 DEGs in OC. (A) Forest plots of 13 DEGs with survival analyses regarding OS, PFS, and PPS using TCGA-OV dataset; (B) survival analyses of BRCA2, BUB1B, and KIF20A regarding OS, PFS, and PPS using TCGA-OV dataset. Red, high-expression group; Black, low-expression group. p-value is log-ranked. Auto-selected best cutoff was used.

Figure 3

Expression profiles of mitotic kinesin superfamily in OC. (A) mRNA levels of ten overexpressed mitotic KIFs (4A, 11, 14, 15, 18A, 18B, 20A, 23, C1, and 2C) in ovarian cancer and normal ovarian tissues from TCGA-OV (n = 426) and GTEx-OV (n = 88) dataset, respectively. TPM, transcripts per million; * p < 0.05; (B) Immunohistochemistry images of ten overexpressed mitotic KIFs in ovarian cancer and normal ovarian tissues from Human Protein Atlas. Red, green, yellow, and black dots present high, medium, low staining, and not detectable, respectively. KIFs (4A, 11, 14, 15, 18B, C1, and 2C) protein were not expressed in normal ovarian tissues; KIF18A and KIF20A have low expression in cytoplasmic/membranous. KIF23 has relative high expression in cytoplasmic/membranous. KIFs (4A, 11, 14, 18A, 18B, 20A, and 23) have high expression in OC tissues, and KIF15 and KIFC1 have medium expression, whereas KIF2C expression level is relatively low in OC tissues.

Figure 4

Genetic alterations and cancer-related pathways of ten overexpressed mitotic KIFs in OC. (A) Genetic alterations of ten overexpressed mitotic KIFs in OC (cBioPortal). Genetic mutation events include missense mutation, amplification, and deep deletion. KIF14 and KIF2C rank the relatively highest two genes of genetic alterations, and their mutation rates are both 7%; (B) the roles of ten overexpressed mitotic KIFs in the famous cancer-related pathways (GSCALite). The red, turquoise, and grey parts present activation, inhibition, and none, respectively.

Figure 5

Transcription profiles of ten overexpressed mitotic KIFs in OC clinicopathological subgroup analysis (UALCAN). Sample numbers of each stage: stage 1 (n = 1); stage 2 (n = 20); stage 3 (n = 243); and stage 4 (n = 38). * p < 0.05.

Figure 6

Prognostic values of ten overexpressed mitotic KIFs in OC. (A) Survival analyses of ten overexpressed mitotic KIFs regarding OS using TCGA-OV dataset. Red, high-expression group; Black, low-expression group. p-Value is log-ranked. Auto-selected best cutoff is used. Forrest plots of relationship between prognosis (B) OS, (C) PFS, (D) PPS, and ten overexpressed mitotic KIFs mRNA expression in patients with different OC clinicopathological features, including grades and stages.

Figure 7

Prognostic values of ten overexpressed mitotic KIFs in OC chemotherapies. Forest plots of relationship between prognosis (A) OS, (B) PFS, (C) PPS, and ten overexpressed mitotic KIFs mRNA expression in patients with different OC chemotherapies using TCGA-OV dataset. (D) Drug resistance analyses of overexpressed mitotic KIFs. The expression of each gene was performed by Spearman correlation analysis with the small molecule/drug sensitivity (IC50). The positive correlation means that the gene high expression is resistant to the drug and vice versa.