SPC25 promotes hepatocellular carcinoma metastasis via activating the FAK/PI3K/AKT signaling pathway through ITGB4

Abstract

Hepatocellular carcinoma (HCC) is a malignant tumor with a high metastatic rate. Recent studies have shown that the mitosis-associated spindle-assembly checkpoint regulatory protein spindle pole body component 25 homolog (SPC25) promotes HCC progression, although the underlying mechanism has yet to be fully elucidated. The aim of the present study was to investigate the mechanism through which SPC25 may promote HCC progression in greater detail. First, the expression of SPC25 was analyzed in publicly available databases to explore the association between SPC25 and HCC metastasis. Western blotting was subsequently performed to examine the level of SPC25 expression in different HCC cell lines. SPC25 was then silenced in HCCLM3 and Huh7 cells, and the effects of SPC25 silencing were investigated using cell proliferation, wound-healing, Transwell migration assays and an in vivo mouse model. Finally, the mechanism of SPC25 action with respect to the promotion of HCC metastasis was explored using microarray analysis and rescue experiments. The results obtained demonstrated that SPC25 is highly expressed in HCC, and this high level of expression is associated with poor prognosis and metastasis. Moreover, SPC25 silencing led to a marked inhibition of the invasion and migration of HCC cells both in vitro and in vivo. The gene-expression profiling and mechanistic experiments suggest that SPC25 preferentially influences the expression of genes associated with extracellular matrix (ECM)-integrin interactions, including integrin subunit β4 (ITGB4), an upstream element of the integrin pathway. ITGB4 upregulation partly reversed the decline in cell invasion and migration capacities that resulted from SPC25 silencing. Furthermore, deleting both SPC25 and ITGB4 caused a decrease in the phosphorylation of focal adhesion kinase (FAK), phosphoinositide 3-kinase (PI3K) and AKT, which are downstream elements of the integrin pathway. Taken together, the results of the present study demonstrated the important role of SPC25 as a prognostic indicator and as a promoter of metastasis in HCC, and the underlying mechanism of its action has been partially elucidated, suggesting that SPC25 could be used as a biomarker and as a target for therapeutic intervention in the treatment of HCC.

Undernutrition Disrupts Cecal Microbiota and Epithelium Interactions, Epithelial Metabolism, and Immune Responses in a Pregnant Sheep Model

“…The altered substance metabolism induced by malnutrition affects epithelial cell proliferation and apoptosis, thus affecting epithelial tissue morphology, but the specific signaling regulatory mechanisms are not clear. ECM plays an important role in the regulation of cellular phenotype and behavior through ECM-cell interactions based on ECM receptors on the cell membrane ( 40 ). ECM-cell interactions mediate cell adhesion and cell signaling and then regulate cell proliferation, differentiation, migration, and apoptosis ( 40 ).…”

“…ECM plays an important role in the regulation of cellular phenotype and behavior through ECM-cell interactions based on ECM receptors on the cell membrane ( 40 ). ECM-cell interactions mediate cell adhesion and cell signaling and then regulate cell proliferation, differentiation, migration, and apoptosis ( 40 ). In the current study, most of the DEGs related to ECM and ECM-receptor interactions were downregulated in the cecal epithelium upon undernutrition, which might result from the inhibition of biological processes in the microbiota ( Fig.…”

“…3d ). ECM can induce FAK activation and promote PI3K phosphorylation ( 40 ). The PI3K signaling pathway plays an important role in cell proliferation, differentiation, and apoptosis ( 41 ).…”

Loss of MTA2‐mediated downregulation of PTK7 inhibits hepatocellular carcinoma metastasis progression by modulating the FAK‐MMP7 axis

“…32 FAK activation is reported to mediate spindle pole body component 25 homolog (SPC25)-promoted HCC progression. 33 PRL-3 is significantly overexpressed and contributes to HCC malignant behaviors via the FAK signaling pathway. 34 FAK inhibitor was shown to promote PD-L1 expression and boost anti-PD1 immunotherapy in an HCC mouse model.…”

“…FAK deactivation promoted by the direct binding of DUSP22 to FAK is essential for DUSP22‐mediated NASH progression 32 . FAK activation is reported to mediate spindle pole body component 25 homolog (SPC25)‐promoted HCC progression 33 . PRL‐3 is significantly overexpressed and contributes to HCC malignant behaviors via the FAK signaling pathway 34 .…”