Cai Chenhui, Zhang Ying, Hu Xu, Yang Sizhen, Ye Jiawen, Wei Zihan, Chu Tongwei
Department of Orthopedics, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
J Clin Transl Hepatol. 2022 Aug 28;10(4):627-641. doi: 10.14218/JCTH.2021.00216. Epub 2022 Jan 4.
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.
Bioinformatics analyses were performed using TCGA, ONCOMINE, HCCDB, Kaplan-Meier plotter, STRING, GEPIA databases. qRT-PCR, western blot, and functional assays were utilized for experiments.
We found remarkable upregulation of transcripts of SKA family genes in HCC samples compared with normal liver samples on bioinformatics analyses and validation. Interaction 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. Transcriptional levels of SKA family members were positively associated with histologic grade, T stage, and α-fetoprotein in HCC patients. Receiver operating characteristic curve analysis 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 functional assays revealed SKA1 acts an important regulatory role in tumor malignant behavior.
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 direction for SKA-targeted immunotherapeutics for HCC.
肝细胞癌（HCC）是最常见的恶性肿瘤之一。纺锤体和动粒相关（SKA）家族基因对于有丝分裂期间中期板的维持和纺锤体检查点沉默至关重要。最近的研究表明，SKA家族基因的失调通过调节细胞周期和DNA复制诱导肿瘤发生、肿瘤进展和化疗耐药性。然而，SKA在HCC背景下的差异转录及其预后意义尚未得到证实。
使用TCGA、ONCOMINE、HCCDB、Kaplan-Meier plotter、STRING、GEPIA数据库进行生物信息学分析。采用qRT-PCR、蛋白质印迹法和功能测定进行实验。
在生物信息学分析和验证中，我们发现与正常肝脏样本相比，HCC样本中SKA家族基因的转录本显著上调。相互作用分析和富集分析表明，SKA家族成员主要与微管运动活性、有丝分裂和细胞周期有关。免疫浸润分析显示所有SKA家族基因与各种免疫细胞亚群相关，尤其是辅助性T细胞2（Th2）。HCC患者中SKA家族成员的转录水平与组织学分级、T分期和甲胎蛋白呈正相关。受试者工作特征曲线分析表明SKA1/2/3对HCC具有很强的预测能力。这些SKA表达的增加与不良的总生存期、无进展生存期和疾病特异性生存期相关。在Cox比例风险回归分析中，SKA1上调和病理分期是HCC患者总生存期和疾病特异性生存期的独立预测因素。最后，临床组织微阵列验证和功能测定表明SKA1在肿瘤恶性行为中起重要调节作用。
SKA家族成员可能在HCC背景下作为诊断和预后标志物。SKA与免疫细胞浸润之间的相关性为HCC的SKA靶向免疫治疗提供了一个有前景的研究方向。
