Prognostic value of Holliday junction-recognizing protein and its correlation with immune infiltrates in lung adenocarcinoma

Abstract

Lung adenocarcinoma (LUAD) is a disease with high morbidity and mortality rates globally. Holliday junction-recognizing protein (HJURP) has recently been shown to be a potentially useful biomarker for diagnosing and determining the progression and prognosis of different cancer types. The present study assessed the prognostic value of HJURP expression in LUAD and investigated the biological pathways related to HJURP that are involved in LUAD pathogenesis. It was found that high HJURP expression was significantly associated with stage (P=0.001), T grade (P=0.012) and N grade (P=0.012). Overall survival analysis demonstrated that patients with LUAD and high HJURP expression had a worse prognosis compared with those patients with low HJURP expression (P<0.001). Multivariate analysis using the Cox proportional hazards model indicated that the expression of HJURP [hazard ratio (HR), 1.32; 95% confidence interval (CI), 1.09-1.60; P=0.004] and stage (HR, 1.90; 95% CI, 1.19-3.03; P=0.007) were independent prognostic factors for patients with LUAD. Gene set enrichment analysis results showed that genes involved with 'basal transcription factors', the 'cell cycle', 'homologous recombination', 'non-small cell lung cancer' (NSCLC), 'oocyte meiosis', 'p53 signaling pathway', 'pathways in cancer', 'RNA degradation' and 'spliceosome' were differentially enriched in the high HJURP expression phenotype. Significant correlations were also found between HJURP and several tumor-infiltrating immune cells, immunomodulators and immune subtypes. Furthermore, western blotting and qPCR analyses confirmed that HJURP was significantly increased in cell lines of NSCLC. In summary, HJURP may be a potentially useful prognostic molecular biomarker of a poor prognosis in LUAD cases. Further experiments are needed to demonstrate the biological effects of HJURP.

Keywords: HJURP; immune infiltration; lung adenocarcinoma; prognosis.

Figure 1.

Differential HJURP expression. (A) Scatter plot and (B) paired plot showing the difference in HJURP expression between normal and tumor samples. The HJURP (NP_060880.3:S473) proteomic expression profile based on (C) sample type and (D) tumor grade (data acquired from UALCAN database where n=105 only). HJURP, Holliday junction-recognizing protein; CPTAC, Clinical Proteomic Tumor Analysis Consortium.

Figure 2.

Associations between HJURP expression and clinicopathological characteristics. (A) T grade, (B) N grade, (C) M status and (D) clinical stage. HJURP, Holliday junction-recognizing protein.

Figure 3.

Kaplan-Meier curves showing the effect of high and low HJURP expression on overall survival in patients with lung adenocarcinoma in The Cancer Gene Atlas cohort. HJURP, Holliday junction-recognizing protein.

Figure 4.

Enrichment plots from the gene set enrichment analysis. Gene set enrichment analysis results showing that ‘basal transcription factors’, ‘cell cycle’, ‘homologous recombination’, ‘non-small cell lung cancer’, ‘oocyte meiosis’, ‘p53 signaling pathway’, ‘pathways in cancer’, ‘RNA degradation’ and ‘spliceosome’ are differentially enriched in Holliday junction-recognizing protein-related lung adenocarcinoma.

Figure 5.

Spearman correlations between the expression of HJURP and TILs across different human cancer types. (A) Relationships between the expression of HJURP and 28 types of TILs across different human cancer types. (B-F) Significant results were found for HJURP expression with regard to the abundance of memory B cells, type 2 T-helper cells, activated CD8 T cells, and CD56(dim) natural killer cells; however, only the abundance of activated CD4 T cells was notably correlated. HJURP, Holliday junction-recognizing protein; TILs, tumor-infiltrating lymphocytes; LUAD, lung adenocarcinoma; Act, activated; Mem B, memory B cells; Th2, type 2 T-helper cells; exp, expression.

Figure 6.

Correlations between three types of immunomodulators and the expression of HJURP. (A-E) Immune-inhibitors, (F-R) immunostimulators and (S and T) major histocompatibility complex molecules. HJURP, Holliday junction-recognizing protein; LUAD, lung adenocarcinoma; exp, expression.

Figure 7.

Distribution of HJURP expression across immune subtypes. (A) Associations between HJURP expression and immune subtypes across different human cancer types. (B) Distribution of HJURP expression across immune and molecular subtypes. HJURP, Holliday junction-recognizing protein; LUAD, lung adenocarcinoma; exp, expression.

Figure 8.

Expression level of HJURP in non-small cell lung cancer. (A and B) HJUPR protein expression was analyzed by western blotting. (C) HJUPR mRNA expression was detected by quantitative PCR. ***P<0.001 vs. control group (BEAS-2B). HJURP, Holliday junction-recognizing protein.

Figure 9.

Flow chart of research design showing the use of clinical and transcriptome data, and the assessment processes. HJURP, Holliday junction-recognizing protein; LUAD, lung adenocarcinoma; qPCR, quantitative PCR.