Hepatocellular carcinoma (HCC) is a common malignancy with high lethality in world-wide. The incidence of HCC development is related closely to chronic inflammation involving in tumor microenvironment and complicated signaling transduction. It has been shown that the transcription factors NF-kB and STAT3, both of which play an important role in the inflammatory pathway, are activated in HCC. Centrosomal P4.1-associated protein (CPAP) plays a vital role in centrosomal function and is identified as a transcriptional co-activator of NF-kB or STAT5. However, the molecular mechanisms underlying CPAP function in liver cancer inflammation remain unclear.
By reporter assay, Q-PCR, immunoblotting and ELISA, the activity of NF-kB or STAT3 in HCC cells with overexpressed CPAP is investigated. The proteins interaction and complex formation between CPAP and NF-kB/STAT3 are demonstrated by in situ PLA. Specimens from HCC patients are collected and analyzed by Q-PCR or immunoblotting for expressions of CPAP, NF-kB, and STAT3.
In this study, we demonstrated that CPAP is overexpressed in HCC, and that overexpression of CPAP is positively associated with high recurrence and vascular invasion. Notably, we found that overexpressed CPAP increases the activity of NF-kB or STAT3 in HCC cells upon TNF-a or IL-6 stimulation. Further results showed that CPAP directly interacts and form complex with NF-kB or STAT3. The expression of CPAP and NF-kB or STAT3 is positively correlated in human clinical HCC specimens. Interestingly, overexpressed CPAP augments the expression of pro-inflammatory cytokines and promotes tumor growth as well as metastasis in the orthotopic and splenic mouse models. Expression of CPAP is positively correlated with plasma pro-inflammatory cytokines expression in HCC patients.
Taken together, these findings suggest that CPAP contributes to cancer malignancy by activating TNFa/NF-kB and IL-6/STAT3 pathways and may serve as a target for HCC therapy.
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All authors have declared no conflicts of interest.