Abstract
Background and aimThe proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC).MethodsThe tissue microarray and serum samples from HCC patients were used to investigate the clinical value of PRCC. The biological function and molecular mechanism of PRCC were demonstrated by cell biology, biochemical and animal experiments. The relationship between PRCC and intratumoral heterogeneity (ITH) was analyzed by bioinformatics.ResultsPRCC was highly expressed in HCC tissues and related to the poor prognosis of HCC patients, its contents were elevated in the preoperative sera of HCC patients. PRCC exhibited high application potential as a substitute or adjuvant of alpha-fetoprotein (AFP) for clinical diagnosis of HCC. It had no significant effect on the proliferation of cancer cells, but could inhibit spheroid formation and metastasis of HCC cells in vitro and in vivo. The high ectopic expression of PRCC made cancer cells insensitive to DNA damage, and enhanced the heterogeneity of HCC cells by inhibiting the JNK/ATM/ATR/ATF2 axis. The HCC patients with high PRCC expression had high ITH, which corresponded to a short overall survival in patients.ConclusionsPRCC has high application potential as a substitute or adjuvant of AFP for clinical diagnosis of HCC. The high ectopic expression of PRCC not only caused HCC cells to resist to cell death induced by DNA damage, but also endowed cancer cells with numerous DNA mutations to become increasingly heterogeneous, finally leading to a poor prognosis in HCC patients. These data suggested PRCC could be a promising therapeutic target in HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is currently one of the most common malignant tumors, its morbidity and mortality have remained high for a long time [1]
proline rich mitotic checkpoint control factor (PRCC) is upregulated in hepatocellular carcinoma (HCC) tissues and sera of patients and associated with poor prognosis The expression of PRCC in 12 pairs of HCC and adjacent normal tissues was detected by Western blot
The results showed that the protein level of PRCC in HCC tissues was significantly higher than that in adjacent normal tissues in 10 pairs of clinical samples, and was slightly lower in only one pair of samples, the remaining 1 pair of HCC tissue and adjacent tissue were equivalent expression for PRCC (Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) is currently one of the most common malignant tumors, its morbidity and mortality have remained high for a long time [1]. PRCC (Gene ID: 5546) is a protein element involved in the pre-mRNA splicing process. The recruitment of phosphorylated PRCC to precursor mRNA activates the human spliceosome B complex [6]. PRCC is involved in checkpoint control, colony formation, cell apoptosis, and can interact with mitotic arrest deficient 2-like protein 2 (MAD2B) and transfer it into nucleus to perform function [9]. The proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC)
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