SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway

Abstract

Objectives We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression. Methods The 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. Results The 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. Conclusions SCUBE3 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.

Targeting SCUBE3 in Hepatocellular Carcinoma

“…The authors further found that the expression of SCUBE3 in HCC cells was higher than that in normal hepatocytes [5]. Subsequently, the authors verified that knockdown of SCUBE3 inhibited HCC cell proliferation, promoted apoptosis, and induced cell cycle arrest [5]. Notably, our in vivo experiments demonstrated that knockdown of SCUBE3 inhibited tumor growth in naked mice [5].…”

“…Subsequently, the authors verified that knockdown of SCUBE3 inhibited HCC cell proliferation, promoted apoptosis, and induced cell cycle arrest [5]. Notably, our in vivo experiments demonstrated that knockdown of SCUBE3 inhibited tumor growth in naked mice [5]. Both in vivo and in vitro experiments showed that down-regulation of SCUBE3 expression reduced the proliferation of HCC cells and significantly reduced the occurrence and development of tumors [5].…”

“…2023 Volume 4, Issue 1 27 [5]. The authors further found that the expression of SCUBE3 in HCC cells was higher than that in normal hepatocytes [5]. Subsequently, the authors verified that knockdown of SCUBE3 inhibited HCC cell proliferation, promoted apoptosis, and induced cell cycle arrest [5].…”

“…J Cell Signal. 2023 Volume 4, Issue 1 27 [5]. The authors further found that the expression of SCUBE3 in HCC cells was higher than that in normal hepatocytes [5].…”

“…Surprisingly, an article entitled "SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway" was published by Cancer Cell International. The authors of this article explored the signal peptide-CUB-EGFlike domain-containing protein 3 (SCUBE3), which is closely related to HCC development [5]. SCUBE3, along with SCUBE1 [6] and SCUBE2 [7], is a member of the signal peptide-CUB-EGF-like domain-containing protein (SCUBE) family.…”