High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma

BACKGROUND Spindle and kinetochore-associated complex subunit 3(SKA3)is a malignancyassociated gene that plays a critical role in the regulation of chromosome separation and cell division.However,the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma(HCC)has not been fully elucidated.AIM To investigate the molecular mechanisms underlying the role of SKA3 in HCC.METHODS SKA3 expression,clinicopathological,and survival analyses were performed using multiple public database platforms,and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples.Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC.Furthermore,the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis(ssGSEA)algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC.The response to chemotherapeutic drugs was evaluated by the R package“pRRophetic”.RESULTS We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC.Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival.GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair.Moreover,patients with high SKA3 expression had significantly decreased ratios of CD8+T cells,natural killer cells,and dendritic cells.Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib,sunitinib,paclitaxel,doxorubicin,gemcitabine,and vx-680.CONCLUSION High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC.SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

Spindle and Kinetochore-associated Family Genes are Prognostic and Predictive Biomarkers in Hepatocellular Carcinoma

Background and Aims:Hepatocellular carcinoma(HCC)is one of the most frequent malignant tumors.Spindle and kinetochore-associated(SKA)family genes are essential for the maintenance of the metaphase plate and spindle checkpoint silencing during mitosis.Recent studies have indicated that dysregulation of SKA family genes induces tumorigenesis,tumor progression,and chemoresistance via modulation of cell cycle and DNA replication.However,the differential transcription of SKAs in the context of HCC and its prognostic significance has not been demonstrated.Methods:Bioinformatics analyses were performed using TCGA,ONCOMINE,HCCDB,Kaplan-Meier plotter,STRING,GEPIA databases.qRT-PCR,western blot,and functional as-says were utilized for in vitro experiments.Results:We found remarkable upregulation of transcripts of SKA family genes in HCC samples compared with normal liver samples on bioinformatics analyses and in vitro validation.Inter-action analysis and enrichment analysis showed that SKA family members were mainly related to microtubule motor activity,mitosis,and cell cycle.Immuno-infiltration analysis showed a correlation of all SKA family genes with various immune cell subsets,especially T helper 2(Th2)cells.Tran-scriptional levels of SKA family members were positively as-sociated with histologic grade,T stage,andα-fetoprotein in HCC patients.Receiver operating characteristic curve analy-sis demonstrated a strong predictive ability of SKA1/2/3 for HCC.Increased expression of these SKAs was associated with unfavorable overall survival,progression-free survival,and disease-specific survival.On Cox proportional hazards regression analyses,SKA1 upregulation and pathological staging were independent predictors of overall survival and disease-specific survival of HCC patients.Finally,clinical tissue microarray validation and in vitro functional assays revealed SKA1 acts an important regulatory role in tumor malignant behavior.Conclusions:SKA family members may potentially serve as diagnostic and prognostic markers in the context of HCC.The correlation between SKAs and immune cell infiltration provides a promising research direc-tion for SKA-targeted immunotherapeutics for HCC.