Abstract
CUL4A, a member of the CULLIN family, functions as a scaffold protein for an E3 ubiquitin ligase. It was reported that the CUL4A gene showed amplification in some human primary hepatocellular carcinomas (HCC). However, the exact role of CUL4A in HCC remains unknown. Here, we aimed to investigate the expression and function of CUL4A in HCC development. Through immunohistochemistry study, we showed increased CUL4A expression in HCC tissues. Statistical analysis disclosed an inverse correlation between CUL4A expression and tumor differentiation grade, and patient survival, but a positive correlation with hepatocyte proliferation as well as lymphatic and venous invasion. CUL4A expression in HCC tissues was associated with HBeAg status in patients and upregulated by HBV in HCC cell lines. Further functional assay showed that CUL4A overexpression significantly promoted growth of H22 tumor homografts in BALB/c mice. Consistently, CUL4A knockdown inhibited the proliferation of established HCC cells, accompanied by S-phase reduction and Cyclin A and Cyclin B1 repression. Furthermore, CUL4A siRNA ameliorated the motility of HCC cell lines with altered expression of epithelial-mesenchymal transition (EMT)-associated molecules. Taken together, our findings indicate that CUL4A plays a pivotal role in HCC progression and may serve as a potential marker for clinical diagnosis and target for therapy.
Highlights
Intestine, and muscular tissues[6]
Our data demonstrate that increased CUL4A expression correlates with the progression of Hepatocellular carcinoma (HCC) and CUL4A might be involved in promoting tumor growth and metastasis
We for the first time reported that CUL4A protein expression was significantly upregulated in HCC tissues
Summary
Intestine, and muscular tissues[6]. As a scaffold protein, CUL4A binds with DNA damage binding protein 1 (DDB1) and ring of cullins (ROC1) and constitutes the ubiquitin ligase E3 complex, which mediates the ubiquitination and degradation of specific substrates. High CUL4A expression in node-negative breast cancers[13], lung cancer[14], and ovarian tumours[10], promoted malignant transformation and correlated with shorter overall and disease-free survival. It was reported that, besides tumor growth and metastasis, CUL4A was involved in conferring breast cancer cells to multiple drug resistance (MDR) by upregulating MDR1/P-gp expression[16]. CUL4A, acting as an oncogene, significantly contributes to tumor initiation, and progression. It might be valuable for prognosis and may serve as a target for drug development. High levels of CUL4A were found in HCC tissues and closely correlated with tumor differentiation grade and metastasis. Our findings suggest that CUL4A promotes hepatocarcinogenesis, supporting the idea that CUL4A may become a potential prognostic marker and may serve as a therapeutic target
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