Evaluation of X-Ray Repair Cross-Complementing Family Members as Potential Biomarkers for Predicting Progression and Prognosis in Hepatocellular Carcinoma

Abstract

The X-ray repair cross-complementing (XRCC) gene family has been revealed to participate in the carcinogenesis and development of numerous cancers. However, the expression profiles and prognostic values of XRCCs (XRCC1-6) in hepatocellular carcinoma (HCC) have not been explored up to now. The transcriptional levels of XRCCs in primary HCC tissues were analyzed by UALCAN and GEPIA. The relationship between XRCCs expression and HCC clinical characteristics was evaluated using UALCAN. Moreover, the prognostic values of XRCCs expression and mutations in HCC patients were investigated via the GEPIA and cBioPortal, respectively. Last but not least, the functions and pathways of XRCCs in HCC were also predicted by cBioPortal and DVAID. The transcriptional levels of all XRCCs in HCC tissues were notably elevated compared with normal liver tissues. Meanwhile, upregulated XRCCs expression was positively associated with clinical stages and tumor grades of HCC patients. Survival analysis using the GEPIA database revealed that high transcription levels of XRCC2/3/4/5/6 were associated with lower overall survival (OS) and high transcription levels of XRCC1/2/3/6 were correlated with poor disease-free survival (DFS) in HCC patients. Furthermore, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) demonstrated the possible mechanisms of XRCCs and their associated genes participating in the oncogenesis of HCC. Our findings systematically elucidate the expression profiles and distinct prognostic values of XRCCs in HCC, which might provide promising therapeutic targets and novel prognostic biomarkers for HCC patients.

Figure 1

Transcriptional levels of XRCCs in paracancerous and HCC tissues (UALCAN). Comparison of XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, and XRCC6 mRNA expression in paracancerous (n = 50) and HCC (n = 371) tissues in TCGA database based on data mining via UALCAN. The transcriptional levels of (a) XRCC1, (b) XRCC2, (c) XRCC3, (d) XRCC4, (e) XRCC5, and (f) XRCC6 were significantly upregulated in HCC tissues compared with paracancerous tissues. ^∗∗∗P < 0.001.

Figure 2

Transcriptional levels of XRCCs in paracancerous and HCC tissues (GEPIA). Validation of differential XRCCs expressions in paracancerous (n = 160) and HCC (n = 369) tissues in TCGA and GTEx dataset based on GEPIA. The transcriptional levels of (a) XRCC1, (b) XRCC2, (c) XRCC3, (d) XRCC4, (e) XRCC5, and (f) XRCC6 were remarkably upregulated in HCC tissues compared with paracancerous tissues. P cutoff: 0.001.

Figure 3

Relationship between mRNA expression of XRCCs and clinical stages of HCC patients. mRNA expressions of six XRCCs were remarkably correlated with patients' clinical stages; patients who were in advanced stages tended to express higher mRNA expression of XRCCs. (a–c, e, f) The highest mRNA expressions of XRCC1/2/3/5/6 were found in Stage 3, (d) while the highest mRNA expression of XRCC4 was found in Stage 2. ^∗P < 0.05, ^∗∗P < 0.01, ^∗∗∗P < 0.001.

Figure 4

Association of mRNA expression of XRCCs with tumor grades of HCC patients. mRNA expressions of 6 XRCCs were significantly related to tumor grades, and as tumor grades increased, the mRNA expressions of XRCCs tended to be higher. (a, d–f) The highest mRNA expressions of XRCC1/4/5/6 were found in tumor Grade 4, (b, c) while the highest mRNA expression of XRCC2/3 was found in Grade 3. ^∗P < 0.05, ^∗∗P < 0.01, ^∗∗∗P < 0.001.

Figure 5

Prognostic value of XRCCs mRNA in HCC patients (OS). OS curves were plotted to evaluate the prognostic value of XRCCs mRNA expression. High mRNA expressions of (b) XRCC2, (c) XRCC3, (d) XRCC4, (e) XRCC5, and (f) XRCC6 were significantly associated with poor OS, while the expression of (a) XRCC1 had no association with OS of HCC patients.

Figure 6

Prognostic value of XRCCs mRNA in HCC patients (RFS). RFS curves were plotted to evaluate the prognostic value of XRCCs mRNA expression. High mRNA expressions of (a) XRCC1, (b) XRCC2, (c) XRCC3, and (f) XRCC6 were remarkably associated with worse DFS, while the expression of (d) XRCC4, and (e) XRCC5 had no associations with DFS of HCC patients.

Figure 7

Correlation between the genetic alterations of XRCCs and prognosis of HCC patients. (a) OncoPrint in cBioPortal database exhibited the proportion and distribution of specimens with genetic alterations in XRCCs. Genetic alterations in XRCCs were notably associated with shorter (b) OS and (c) DFS of HCC patients.

Figure 8

Predicted pathways of XRCCs and their 36 frequently altered neighbor genes in HCC patients. The network of XRCCs and their 36 frequently altered neighbor genes were constructed. The total 36 genes were frequently affected by XRCCs alterations.

Figure 9

GO analysis of XRCCs and their associated genes. Gene Ontology (GO) enrichment analysis predicted the functional roles of target host genes based on three aspects including (a) biological processes (BP), (b) cellular components (CC), and (c) molecular functions (MF). Top 10 terms of BP, CC, and MF analysis were represented in this figure.

Figure 10

KEGG analysis of XRCCs and their associated genes. The functions of XRCCs and genes significantly associated with XRCCs alterations were predicted by analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG). The top 10 terms of KEGG analysis were represented in this figure.