HMGB1 reduce DNA damage by binding KU70 to activate NHEJ pathway in colorectal cancer cells after radiation

by Xiuxin Liu, Yuhui Han, Ruixue Kuang, Wenjiong Sheng, Yan Zhang, Xinyu Jia, Xiaoxiao Gao, Yanchao Ma

DNA damage-induced by radiotherapy is a critical factor in promoting the death of colorectal cancer cells (CRC). Although high mobility group box 1 (HMGB1) reportedly plays a vital role in tumor radioresistance by modulating DNA damage repair, the precise mechanisms remain unclear. In this study, HMGB1 knockdown markedly enhanced cell apoptosis after radiation. HMGB1 downregulation significantly inhibited DNA damage repair and reactive oxygen species (ROS)-mediated redox homeostasis after irradiation in CRC cells. Mechanistically, HMGB1 interacts with KU70 via its region spanning residues 95–163. This interaction subsequently activates the non-homologous end joining (NHEJ) pathway to facilitate DNA damage repair, ultimately leading to reduced radiation-induced cell apoptosis. KU70 silencing showed the same effect as HMGB1 depletion mediated cell apoptosis and DNA damage response both in vitro and in vivo. Additionally, HMGB1 and KU70 were overexpressed in CRC tissues. Analysis of the GEPIA database indicated that elevated levels of both genes showed a trend toward association with poor patient prognosis, although this did not reach statistical significance. The current study revealed that HMGB1 may promote DNA damage repair through KU70 and its mediated NHEJ pathway to affect apoptosis in CRC cells after irradiation. Thus, targeting the HMGB1/KU70/NHEJ axis may be a potential therapeutic target to promote the response of CRC to radiotherapy and in-depth study of the specific mechanism of this axis in CRC radioresistance will help to the develop more effective treatment strategies.

Transcriptome profiling indicates varied gene responses to <i>Pasteurella multocida</i> mutant infections in cattle

by Hao Ma, Fred M. Tatum, Robert E. Briggs, Rohana P. Dassanayake, Tasia M. Kendrick, Eduardo Casas

Pasteurella multocida is a pathogen that causes bovine respiratory disease, and the development of an effective vaccine is important for improving animal health. Live-attenuated vaccines induce a long-lasting immune response with minimal side effects. The objective of this study was to evaluate potential live vaccine candidates from three P. multocida mutants produced by separately disrupting the genes of filamentous hemagglutinin 2 (fhaB2), hydrogenase-1 operon (hyaE), and n-acylneuraminate-9-phosphatase (nanP) of a serogroup 3 strain (P1062, WT) by clinical testing and transcriptome analysis. Challenge with WT and the three mutants conferred protection against P. multocida, with less lung lesions (4.7–6.2%) compared to 22.4% in the sham group. Transcriptome analysis identified 807 differentially expressed protein-coding transcripts (DETs) in the blood and 6473 DETs in the liver compared to the sham, WT, and each of the mutants. In total, 15 and 64 differentially expressed microRNAs (DEmiRNAs) and 12 and 74 differentially expressed long non-coding RNAs (DElncRNAs) were identified in blood and liver, respectively. The DEmiRNAs were not significantly associated with the DETs within each comparison. DElncRNAs were associated with 12 and 170 DETs in blood and liver respectively. The greatest number of unique DETs were found between hyaE and sham groups in the liver, which agreed with the low colonization rate in the nares and palatine tonsils. For the DETs between sham and WT the under-enriched gene ontology terms in blood were all included in the liver for the DETs identified by WT vs. sham, nanP vs. sham, and hyaE vs. sham, and were related to the signaling pathway, stimulus, and sensory perceptions in biological processes with the molecular function of olfactory receptor activity. The number of identified DETs, decreased percentage of lung lesions, and colonization rates indicate that fhaB2 could be a promising vaccine candidate.