SKA3 Promotes tumor growth by regulating CDK2/P53 phosphorylation in hepatocellular carcinoma

Abstract

Spindle and kinetochore-related complex subunit 3 (SKA3) is a component of the spindle and kinetochore-related complexes and is essential for accurate timing of late mitosis. However, the relationship between SKA3 and hepatocellular carcinoma (HCC) has not yet been fully elucidated. Gene expression omnibus (GEO) (GSE62232, GSE45436, GSE6764, and GSE36376) and The Cancer Atlas (TCGA) datasets were analyzed to identify differential expression genes. Cell proliferation ability was analyzed using Cell Counting Kit-8 (CCK8) assay and plate clone formation assay, while scratch wound healing assay and transwell assay were used to analyze cell invasion. The role of SKA3 in vivo was explored using subcutaneous xenotransplantation model and lung metastasis model. Bioinformatics analysis found that hepatocellular carcinoma patients with high levels of expression of SKA3 have a poor prognosis. Similarly, immunohistochemical staining of 236 samples of tumors also found higher SKA3 expression in them, than in adjacent normal liver tissues. Significant levels of inhibition of in vivo and in vitro tumor proliferation and invasion result from the downregulation of SKA3. Mechanistically, SKA3 was found to affect tumor progression through the cell cycle and P53 signaling pathway as shown by the gene enrichment analysis (GSEA). G2/M phase arrest and severe apoptosis was also found to result from SKA3 knockdown, as shown by the inhibition of CDK2/p53 phosphorylation together with downregulation of BAX/Bcl-2 expression in HCC cells. Overall, these findings uncover the role of SKA3 in regulating the apoptosis and proliferation of hepatocellular carcinoma cells. This study was able to uncover new information on the tumorigenesis mechanism in hepatocellular carcinoma.

Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

“…However, according to our results, SKA3 proteins in uenced the progression of HCC and PAAD tumors. Therefore, we speculated that SKA3 could have different biological functions in both tumors, an observation that is contrary to previous studies [22,27].…”

“…expression is higher in HCC tumor tissues than in para-carcinoma [27]. Hou et al reported that SKA3 was up-regulated in HCC tissues and that downregulation of SKA3 mRNA was associated with better survival of HCC [27].…”

Identification of 13 Key Genes Correlated With Progression and Prognosis in Hepatocellular Carcinoma by Weighted Gene Co-expression Network Analysis

“…Recently, a study showed that down-regulation of SKA3 could inhibit HCC proliferation and invasion in vivo and in vitro. On the basis of gene enrichment analysis (GSEA), SKA3 was enriched in the cell cycle and P53 signaling pathways and these results were verified (Hou et al, 2019). Moreover, it has been reported that SKA3 can facilitate PI3K/AKT signaling pathway to promote cell cycle and progression in cervical cancer (Hu et al, 2018).…”

Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1–AKT axis-mediated glycolysis

“…As an important component of the spindle and kinetochore-related complexes 29 , SKA3 is essential for regulating mitosis with NDC80 complex and thus controlling cell proliferation and apoptosis 26 , 30 . Aberrant expression of SKA3 is closely associated with tumorigenesis and development 14 , 30 . For instance, SKA3 binds EGFR and consequently activates PI3K–AKT, thus promoting lung adenocarcinoma metastasis 14 .…”