MP33-04 HMGB1 PROMOTES TUMOR PROGRESSION AND INVASION THROUGH HMGB1/TNFR1/NF-ΚB AXIS IN CASTRATION-RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-04 HMGB1 PROMOTES TUMOR PROGRESSION AND INVASION THROUGH HMGB1/TNFR1/NF-ΚB AXIS IN CASTRATION-RESISTANT PROSTATE CANCER Ae Ryang Jung, Yong Hyun Park, Dong Ho Shin, Hyong Woo Moon, U-Syn Ha, Sung-Hoo Hong, Ji Youl Lee, and Sae Woong Kim Ae Ryang JungAe Ryang Jung More articles by this author , Yong Hyun ParkYong Hyun Park More articles by this author , Dong Ho ShinDong Ho Shin More articles by this author , Hyong Woo MoonHyong Woo Moon More articles by this author , U-Syn HaU-Syn Ha More articles by this author , Sung-Hoo HongSung-Hoo Hong More articles by this author , Ji Youl LeeJi Youl Lee More articles by this author , and Sae Woong KimSae Woong Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is the most common male cancer. Most patients treated with androgen deprivation therapy progress to castration-resistant PCa. To overcome the limitations of the current treatment, identification of more effective treatment targets is urgently needed. High mobility group box 1 protein (HMGB1) is known to be associated with progression, metastasis, and poor prognosis of several solid tumors; however, the role of HMGB1 in PCa remains unclear. Thus, we aimed to evaluate the clinical significance and biological mechanism of HMGB1 in PCa. METHODS: After transient transfection of PC3 and DU-145 cells with HMGB1 siRNA, diverse experiments were performed to evaluate the changes in proliferation, apoptosis, invasion. We subsequently investigated whether HMGB1 downregulation could affect NF-κB signaling in PCa cells using a human NF-κB proteome profiler array. To identify the TNFR responsible for HMGB1 binding, we performed a Co-IP assay on HEK293 cells following co-transfection with FLAG-HMGB1 and HA-TNFR1, 3, or 5. Finally, we determined the impact of HMGB1 on overall survival in PCa using the Cancer Genome Atlas (TCGA) datasets. We further validated the prognostic importance of HMGB1 by immunofluorescence staining in 131 PCa patients from the Korean Prostate Bank. RESULTS: The inhibition of HMGB1 expression significantly reduced cell proliferation, invasive capacity, and NF-κB signaling pathway in vitro. Our results showed that HMGB1 is a critical factor in the development and progression of PCa. Moreover, we found that HMGB1 directly interacts with TNFR1, and TNFR1 overexpression in HMGB1 knockdown cells reversed the effects of HMGB1 knockdown. In TCGA 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 results suggest that HMGB1 binding to TNFR1 promotes tumor progression by activating the NF-κB signaling pathway in PCa, and HMGB1/TNFR1/NF-κB signaling pathway could serve as a novel therapeutic target for improving PCa therapy. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e607-e607 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ae Ryang Jung More articles by this author Yong Hyun Park More articles by this author Dong Ho Shin More articles by this author Hyong Woo Moon More articles by this author U-Syn Ha More articles by this author Sung-Hoo Hong More articles by this author Ji Youl Lee More articles by this author Sae Woong Kim More articles by this author Expand All Advertisement Loading ...