Abstract
Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.
Highlights
Because our studies showed that Centrosomal P4.1-associated protein (CPAP)/PN1 and A5C fragments interact with the STAT3 SH2 domain upon IL-6 treatment (Fig. 4f-ii), we hypothesized that overexpression of GFP-PN1 may compete with CPAP for interacting with STAT3
Our results showed that IL-8 expression is increased in CPAP-overexpressing hepatocellular carcinoma (HCC) cells (Fig. 4a, b)
We investigated the effect of IL-8 on CPAP-enhanced IL-6/STAT3-mediated metastasis
Summary
During HCC development, angiogenesis plays an important role in promoting tumor growth and metastasis, which leads to malignancy and poor prognoses [2, 3]. To investigate the role and underlying mechanism of CPAP in angiogenesis and metastasis in HCC, orthotopic and splenic injection animal models were performed, and it was found that CPAP could enhance tumor growth and metastasis in vivo. Both ex vivo and in vivo experimental results indicated that CPAP overexpression promotes tumor growth, metastasis, and angiogenesis by enhancing STAT3 transcriptional activity via direct interactions. Our studies indicated that CPAP overexpression correlates with HCC malignancies and can serve as a prognostic indicator for HCC patients
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