Effects of Holliday Junction-Recognition Protein-Mediated C-Jun N-Terminal Kinase/ Signal Transducer and Activator of Transcription 3 Signaling Pathway on Cell Proliferation, Cell Cycle and Cell Apoptosis in Bladder Urothelial Carcinoma.

The Holliday Junction-Recognition Protein (HJURP) was upregulated in several tumors, which was associated with poor outcome. This study investigated the effects of the HJURP-mediated c-Jun N-terminal kinase (JNK)/ signal transducer and activator of transcription 3 (STAT3) pathway on bladder urothelial carcinoma (BLUC). Online databases were used to analyze HJURP expression in BLUC and the correlation of HJURP to JNK1 [mitogen-activated protein kinase 8 (MAPK8)], JNK2 (MAPK9), STAT3, marker of proliferation Ki-67 (MKI67), proliferating cell nuclear antigen (PCNA), cyclin dependent kinase 2 (CDK2), CDK4 and CDK6. HJURP expression was detected in BLUC cells and human normal primary bladder epithelial cells (BdECs). BLUC cells were treated with HJURP lentivirus activation /shRNA lentivirus particles or JNK inhibitor SP600125. HJURP was upregulated in BLUC tissues and correlated with poor prognosis of patients (all P < 0.05). HJURP in tumor positively correlated with MAPK8 (R = 0.30), MAPK9 (R = 0.30), STAT3 (R = 0.15), MKI67 (R = 0.60), PCNA (R = 0.46), CDK2 (R = 0.39), CDK4 (R = 0.24) and CDK6 (R = 0.21). The JNK inhibitor SP600125 decreased p-JNK/JNK and p-STAT3/STAT3 in BLUC cells, which was reversed by HJURP overexpression (P < 0.05). The HJURP-mediated JNK/STAT3 pathway promoted BLUC cell proliferation and inhibited cell apoptosis (P < 0.05). HJURP reversed the arrested G0/G1 phase of BLUC cells by SP600125. HJURP acted as an oncogene to regulate BLUC cell proliferation, apoptosis and the cell cycle by mediating the JNK/STAT3 pathway. Therefore, HJURP targeting might be an attractive novel therapeutic target for early diagnosis and treatment in BLUC.

A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors.

Although cell-based or animal-based research evidence support the association of Holliday junction recognition protein (HJURP) with cancers, no pan-cancer investigation has been reported. The datasets of Gene Expression Omnibus database along with The Cancer Genome Atlas project were used to evaluate the expression of HJURP in various types of tumors. HJURP is overexpressed in a considerable number of cancers, and some changes in DNA methylation and genetic alterations are discovered in some types of tumors, such as kidney-related and adrenal gland-related tumors. Based on PrognoScan and gene expression profiling interactive analysis (GEPIA), the elevated expression of HJURP worsened the survival time of individuals with cancer. The biological general repository for interaction datasets (BioGRID) and The database for annotation, visualization and integrated discovery (DAVID) were used to establish the functional molecular network. It revealed that the cell cycle and p53 signaling pathway are the key molecular mechanisms that HJURP promotes carcinogenesis. The nomograms between HJURP and clinical pathological factors based on the Cox proportional hazards model showed a good prognostic performance in kidney carcinoma, hepatocellular carcinoma, and lung adenocarcinoma. Our first pan-cancer study provides a relatively profound insights into the oncogenic roles of HJURP across different tumors.

Holliday junction recognition protein as a prognostic biomarker and therapeutic target for oral cancer.

Since oral cancer (OC) is highly malignant and the efficacy of standard treatments is limited, the development of new therapeutics is urgently awaited. To identify potential molecular targets for new OC diagnosis and therapies, we screened oncoantigens by gene expression profile and focused on Holliday junction recognition protein (HJURP), a mammalian centromere­specific chaperone. HJURP was found to be highly expressed in the majority of OC cell lines and tissues as compared to normal oral epithelial cells. Tissue microarray analysis confirmed that HJURP was expressed in 103 (67.8%) of 152 OC tissue specimens, but expression in normal oral tissues was limited. Positive HJURP expression was significantly correlated with shorter overall survival (P=0.003). Depletion of HJURP by small­interfering RNAs dramatically inhibited the growth of OC cells by inhibition of cell cycle progression and induced senescence of OC cells. In addition, inhibition of the interaction between HJURP and CENP­A significantly suppressed the growth of OC cells. These results indicate that HJURP is a potential prognostic biomarker, and targeting HJURP and its molecular pathway presents a new strategy for the development of treatments against OC.

Holliday junction­recognition protein modulates apoptosis, cell cycle arrest and reactive oxygen species stress in human renal cell carcinoma.

Holliday junction recognition protein (HJURP) is involved in the regulation of mortality in various cell types, including renal cell carcinoma (RCC) cells. The specific mechanisms by which HJURP regulates RCC cell apoptosis and the cell cycle have not been previously investigated, to the best of our knowledge. In the present study, the expression of HJURP in RCC tissues and adjacent paracancerous renal tissue, as well as in RCC cell lines, was analyzed using reverse transcription­quantitative PCR and western blot analysis. The A498 RCC cells were transfected with an HJURP overexpression vector, which resulted in reduced proliferation, as demonstrated using immunofluorescence staining, a Cell Counting Kit­8 assay and a colony formation assay. Flow cytometry and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labelling assays were used to determine the effect of HJURP on the cell cycle and apoptosis of RCC cells. Proteins associated with the reactive oxygen species (ROS) status were analyzed using western blot analysis. The expression of HJURP was lower in RCC tissues and cells compared with that in the adjacent paracancerous renal tissues and control cells. Furthermore, overexpression of HJURP resulted in a decrease in cell viability and proliferation in vitro. Overexpression of HJURP resulted in cell cycle arrest at the G0/G1 phase, cell apoptosis and an increase in ROS stress. In addition, the phosphorylated/total sirtuin 1 (SIRT1) protein ratio was decreased, whereas the expression of peroxisome proliferator­activated receptor (PPAR)γ was increased in the HJURP­overexpressing RCC cells. In clinical practice, decreased HJURP expression may be associated with poor prognosis in patients with RCC. These results suggest that HJURP may regulate cell apoptosis and proliferation in RCC cells and this may be mediated by PPARγ/SIRT1. Thus, HJURP may be used as a predictor of prognosis in patients with RCC.

HJURP Promotes Epithelial-to-Mesenchymal Transition via Upregulating SPHK1 in Hepatocellular Carcinoma.

Holliday Junction Recognition Protein (HJURP) is involved in various cancers including hepatocellular carcinoma (HCC). Current studies have showed that HJURP is correlated with HCC proliferation. However, the role of HJURP in HCC Epithelial-to-Mesenchymal Transition remains unclear. In this study, we found that HJURP knockdown significantly reduced the migration and invasion abilities of HCC cells both in vivo and in vitro by interacting with Sphingosine kinase1 (SPHK1). Conversely, HJURP overexpression enhanced these biological abilities. Moreover, high HJURP expression is related to poor prognosis of HCC patients. In conclusion, HJURP plays an important role in tumor metastasis by upregulating SPHK1. And high HJURP expression may predict a lower disease-free survival rate and higher possibility of microvascular invasion in HCC patients.

Upregulation of Holliday junction recognition protein predicts poor prognosis and biochemical recurrence in patients with prostate cancer.

Abnormal expression of Holliday junction recognition protein (HJURP) in several types of tumor cells plays a vital role in the formation and progression of tumors. Few studies have investigated the role of HJURP in prostate cancer (PCa). The aim of this study was to analyze the expression levels of HJURP in PCa and to establish the association with clinicopathological data. Reverse transcription quantitative polymerase chain reaction and immunohistochemical analysis were used to detect the expression levels of HJURP in benign and PCa prostate tissues. The Taylor dataset was statistically analyzed to determine if HJURP expression levels were associated with PCa clinicopathological data. HJURP was overexpressed in PCa tissues compared with benign prostate tissues. Statistical analysis of the Taylor dataset indicated that upregulation of HJURP was significantly associated with positive prostate-specific antigen (PSA) levels (P=0.004), high Gleason score (P=0.005), advanced pathological stage (P=0.007), metastasis (P<0.001) and PSA failure (P<0.001). Higher HJURP mRNA expression levels were significantly associated with shorter biochemical recurrence (BCR)-free survival (P<0.001). To the best of our knowledge, this study is the first report of HJURP upregulation in PCa tissues. Upregulation of HJURP may predict BCR-free survival and HJURP may be an oncogene that impacts the prognosis of patients with PCa.

HJURP regulates cellular senescence in human fibroblasts and endothelial cells via a p53-dependent pathway.

Holliday junction recognition protein (HJURP), a centromere protein-A (CENP-A) histone chaperone, mediates centromere-specific assembly of CENP-A nucleosome, contributing to high-fidelity chromosome segregation during cell division. However, the role of HJURP in cellular senescence of human primary cells remains unclear. We found that the expression levels of HJURP decreased in human dermal fibroblasts and umbilical vein endothelial cells in replicative or premature senescence. Ectopic expression of HJURP in senescent cells partially overcame cell senescence. Conversely, downregulation of HJURP in young cells led to premature senescence. p53 knockdown, but not p16 knockdown, abolished senescence phenotypes caused by HJURP reduction. These data suggest that HJURP plays an important role in the regulation of cellular senescence through a p53-dependent pathway and might contribute to tissue or organismal aging and protection of cellular transformation.