Abstract
ObjectivesWe aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression.MethodsThe role of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were detected using MTT assay, colony formation assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was inspected by a xenograft tumour model in nude mice. The related mechanisms were further studied.ResultsThe level of SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and in vivo. Screening of cell cycle-related proteins revealed that CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFβ signalling pathway and the PI3K/AKT signalling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFβRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signalling pathway and the phosphorylation of GSK3β to inhibit its kinase activity.ConclusionsSCUBE3 promotes HCC development by regulating CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway. In addition, SCUBE3 may be a new molecular target for the clinical diagnosis and treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in men and the seventh most prevalent cancer in women
We found that signal peptide-CUB-epidermal growth factor (EGF)-like domain-containing protein3 (SCUBE3) may promote the proliferation of HCC cells by regulating CCNE1 expression
SCUBE3 is upregulated in HCC and is associated with poor prognosis SCUBE3 expression in normal and cancer tissues was analyzed using The Cancer Genome Atlas (TCGA) liver HCC data on UALCAN
Summary
Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer in men and the seventh most prevalent cancer in women. After the type I receptor is activated, SMAD2 and SMAD3 are activated, which bind to SMAD4 to form heteromers These are transferred to the nucleus where they regulate specific gene transcription responses [10, 12]. This is the typical sequence of events in the classical TGFβ signaling pathway. SCUBE3 is a glycoprotein secreted by cells, which was first identified in human umbilical vein endothelial cells It consists of five motifs: an n-terminal signal peptide, an epidermal growth factor (EGF)-like repeat sequence, a spacer region, three cysteine-rich domains, a complement protein C1r/C1s, and domains of Uegf and Bmp (CUB) c-terminal [15]. SCUBE3 promotes the proliferation of osteosarcoma cells and influences the prognosis of patients with osteosarcoma [19, 20]
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