PCNA-associated factor (KIAA0101/PCLAF) overexpression and gene copy number alterations in hepatocellular carcinoma tissues

Abstract

Background PCNA-associated factor, the protein encoded by the KIAA0101/PCLAF gene, is a cell-cycle regulated oncoprotein that regulates DNA synthesis, maintenance of DNA methylation, and DNA-damage bypass, through the interaction with the human sliding clamp PCNA. KIAA0101/PCLAF is overexpressed in various cancers, including hepatocellular carcinoma (HCC). However, it remains unknown whether KIAA0101/PCLAF overexpression is coupled to gene amplification in HCC. Methods KIAA0101/PCLAF mRNA expression levels were assessed by quantitative real-time PCR (qRT-PCR) in 40 pairs of snap-frozen HCC and matched-non-cancerous tissues. KIAA0101/PCLAF gene copy numbers were evaluated by droplet digital PCR (ddPCR) in 36 pairs of the tissues, and protein expression was detected by immunohistochemistry (IHC) in 81 pairs of formalin-fixed paraffin-embedded (FFPE) tissues. The KIAA0101/PCLAF gene copy number alteration and RNA expression was compared by Spearman correlation. The relationships between KIAA0101 protein expression and other clinicopathological parameters, including Ki-67, p53, and HBsAg protein expression in HCC tissues, were evaluated using Chi-square test. Results Our results demonstrated that KIAA0101/PCLAF mRNA levels were significantly higher in HCC than in the matched-non-cancerous tissues (p < 0.0001). The high KIAA0101/PCLAF mRNA levels in HCC were associated with poor patient survival. The KIAA0101/PCLAF gene was not amplified in HCC, and KIAA0101/PCLAF gene copy numbers were not associated with KIAA0101/PCLAF transcript levels. KIAA0101 protein was overexpressed in the majority of HCC tissues (77.8%) but was not detectable in matched-non-cancerous tissues. Significant correlations between the expression of KIAA0101 protein in HCC tissues and p53 tumor suppressor protein (p = 0.002) and Ki-67 proliferation marker protein (p = 0.017) were found. However, KIAA0101 protein levels in HCC tissues were not correlated with patient age, tumor size, serum AFP level, or the HBsAg expression. Conclusions KIAA0101/PCLAF mRNA and protein overexpression is frequently observed in HCC but without concurrent KIAA0101/PCLAF gene amplification. Significant correlations between the expression of KIAA0101 protein and p53 and Ki-67 proteins were observed in this study. Thus, detection of KIAA0101/PCLAF mRNA/protein might be used, along with the detection of p53 and Ki-67 proteins, as potential biomarkers to select candidate patients for further studies of novel HCC treatment related to these targets.

Pan‑cancer analyses reveal the regulation and clinical outcome association of PCLAF in human tumors

“…More and more studies have confirmed the functional interaction between PCLAF and tumors ( 8 , 10 , 11 , 52 , 53 ). Numerous studies have performed immunohistochemical analysis of various tumor tissues, which strongly suggest that PCLAF is highly expressed in a variety of tumor tissues and may serve as a pan-cancer prognostic biomar ker ( 13 , 42 , 43 , 46 – 50 , 54 , 55 ). Yet, the pathogenesis of PCLAF in different tumors is still unclear, and further research is needed.…”

DNA replication: Mechanisms and therapeutic interventions for diseases

“… 375 , 376 Furthermore, upregulated PCNA is associated with various digestive system tumors including colorectal carcinoma, ESCC, and HCC (Table 5 ). 377 , 378 , 379 …”

“…375,376 Furthermore, upregulated PCNA is associated with various digestive system tumors including colorectal carcinoma, ESCC, and HCC (Table 5). [377][378][379] PCNA is a critical factor in DNA replication and DNA damage repair. Hence, PCNA is a target for designing antiproliferation and anticancer drugs.…”

Proliferating cell nuclear antigen clamp associated factor, a potential proto-oncogene with increased expression in malignant gastrointestinal tumors

“…Gene integrated bioinformatics analysis indicates that PCLAF is one of the core genes associated with HCC[ 52 ]. PCLAF mRNA levels are increased in HCC[ 53 ]. A recent study has shown that PCLAF is involved in the microvascular invasion in HCC by activating epithelial-mesenchymal transition[ 13 ].…”