Expression of HMGB1 in prostate cancer: Clinical and Biological correlations
Sources of Funding: None
Introduction
The high mobility group box1 (HMGB1), which is the important nuclear factor, has been noted to play a critical role of biological processes such as DNA repair, transcription and extracellular response. Increased expression of HMGB1 has been observed in several solid cancers and known to be associated with poor prognosis. However, there have been little studies of the role of HMGB1 in prostate cancer (PCa) development and progression. Therefore, in this study, we aimed to investigate 1) the role of HMGB1 on cellular proliferation, apoptosis, migration, and invasion, 2) the underlying biological mechanisms of HMGB1 in PCa, and 3) the expression pattern of HMGB1 in PCa patients with different stage and grade and its prognostic importance.
Methods
After transient transfection of PC3 and DU-145 cells with HMGB1 siRNA, diverse experiments were performed to evaluate the changes in proliferation, apoptosis, migration and invasion. To determine whether HMGB1 affects the NF-?B pathway, subcellular localizations of p65 and phosphorylated p65 were assessed by western blot analysis. Using the Cancer Genome Atlas (TCGA) datasets, we determined the impact of HMGB1 on overall survival in PCa. We further validated the prognostic importance of HMGB1 by immunofluorescence staining in 131 PCa patients from the Korean Prostate Bank.
Results
Inhibition of HMGB1 expression significantly reduced cell proliferation and increased cell cycle arrest in the sub-Go phase of PC3 and DU-145 cells. It also inhibited the migration and invasive capacity of PCa cells. Western blot analysis showed that inhibition of HMGB1 reduced p65 and phosphorylated p65 protein levels in nuclear fractions of PCa cells. In The Cancer Genome Atlas data set (n = 498), HMGB1 was altered in 61 of 498 patients (12%). Overall survival was shorter in the high HMGB1 expression group (medians: 115.0 months vs. not reached; P = 0.0296). In the Korean Prostate Bank cohort, the positive areas of HMGB1 differed in patients with BPH, and low-, intermediate-, high-risk, and metastatic PCa (4.6, 11.9, 18.6, 19.7, and 23.4%, p?0.001). During the median follow-up of 32 months, increased expression of HMGB1 was associated with a significant decrease in biochemical recurrence free survival on Kaplan-Meier analysis.
Conclusions
Our findings demonstrate an important role of HMGB1 and novel relationship between HMGB1 and NF-?B pathway in PCa. Therapy targeting HMGB-associated pathways may represent a novel therapeutic avenue for PCa.
Funding
None
Ae Ryang Jung
Jin Bong Choi
U-Syn Ha
Sung-Hoo Hong
Sae Woong Kim
Ji Youl Lee