The Role of HMGB1 in Radioresistance of Bladder Cancer

Abstract

Although radical cystectomy surgery is the standard-of-care for muscle-invasive bladder cancer, it entails complete removal of the bladder and surrounding organs which leads to substantial loss in the quality-of-life of patients. Radiotherapy, which spares the bladder, would be a more appropriate treatment modality if we can utilize molecular markers to select patients with better response to radiation. In this study, we investigate a protein called high mobility group box protein 1 (HMGB1) as a predictive marker for radiotherapy response in bladder cancer. Our in vitro results indicate a positive correlation between higher levels of HMGB1 protein and resistance to radiation in various cell lines. Upon HMGB1 protein knockdown, highly significant (>1.5-fold) sensitization to radiotherapy was achieved. We saw that loss of HMGB1 was associated with at least two times higher (P < 0.001) DNA damage in cell lines postradiation. Our results also depicted that autophagy was inhibited more than 3-fold (P < 0.001) upon HMGB1 knockdown, implicating its role in autophagy as another cause of bladder cancer radioresistance. Further validation was done in vivo by conducting mouse tumor xenograft experiments, where HMGB1 knockdown tumors showed a significantly better (P < 0.001) response to radiotherapy and decreased autophagy (shown by P62 staining) as compared with controls. The cumulative findings of our in vitro and in vivo studies highlight the significance of HMGB1 as a radiation response marker as well as its utility in radiosensitization of bladder cancer.

Down-regulation of LncRNA TUG1 enhances radiosensitivity in bladder cancer via suppressing HMGB1 expression

“…HMGB1 knockdown could promote the radiosensitivity of breast cancer cells through breaking telomere homeostasis and inhibiting the repair of DNA damage [12]. Moreover, HMGB1 knockdown markedly sensitize the bladder cancer cells to radiotherapy [33]. However, how it is regulated in radiosensitivity of bladder cancer is not quite clear.…”

Cytolethal Distending Toxin Enhances Radiosensitivity in Prostate Cancer Cells by Regulating Autophagy

“…In addition, a recent study in which HMGB1 was conditionally ablated in mice revealed that HMGB1 is required for the autophagy process (Yanai et al, 2013). Most importantly, the elevation of HMGB1 activates the autophagy pathway and has been implicated in the development of radioresistance in bladder cancer (Shrivastava et al, 2016). Loss of HMGB1 increases DNA damage and sensitizes cancer cells to radiation (Shrivastava et al, 2016).…”

“…Most importantly, the elevation of HMGB1 activates the autophagy pathway and has been implicated in the development of radioresistance in bladder cancer (Shrivastava et al, 2016). Loss of HMGB1 increases DNA damage and sensitizes cancer cells to radiation (Shrivastava et al, 2016). In addition, CDT possesses a genotoxic activity that has been shown to function as a radimimetic agent and prolong persistent levels of DNA damage (Fahrer et al, 2014).…”

Bladder Preservation Therapy: A Review of the Literature and Future Directions

“…54 On a translational level, high mobility group box protein 1 (HMGB1) has been demonstrated to be a predictive marker for resistance to radiotherapy in bladder cancer in vitro models. 55 Knockout of HGMB1 in vivo on mouse tumor xenograft models led to a better response to radiotherapy and decreased autophagy compared to controls. 55 Additionally, DNA damage response gene alterations were associated with significant lower risk of relapse as well as a trend toward lower risk for metastasis and disease progression on multivariate analysis of patients with urothelial histology treated with chemoradiation (median dose 66 Gy).…”

“…55 Knockout of HGMB1 in vivo on mouse tumor xenograft models led to a better response to radiotherapy and decreased autophagy compared to controls. 55 Additionally, DNA damage response gene alterations were associated with significant lower risk of relapse as well as a trend toward lower risk for metastasis and disease progression on multivariate analysis of patients with urothelial histology treated with chemoradiation (median dose 66 Gy). 56 Finally, use of EGFR tyrosine kinase inhibitors has been shown to have a synergistic effect with HER2 kinase inhibitors both in vitro and in vivo to enhance radiosensitivity.…”