HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia.

Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, immunofluorescence, and flow cytometry were used to detect the mitochondrial transfer between HCC cells. We found that mitochondrial transfer between HCC cells was confirmed using tunnel nanotubes (TNTs). The transfer of mitochondria from the highly invasive HCC cells to the less invasive HCC cells could enhance the migration and invasion ability of the latter. The hypoxic conditions increased the mitochondrial transfer between HCC cells. Then the mechanism was identified using co-immunoprecipitation, luciferase reporter assay, and chromatin immunoprecipitation. We found that RHOT1, a mitochondrial transport protein, promoted mitochondrial transfer and the migration and metastasis of HCC cells during this process. Under hypoxia, HMGB1 further regulated RHOT1 expression by increasing the expression of NFYA and NFYC subunits of the NF-Y complex. RAC1, a protein associated with TNTs formation, promoted mitochondrial transfer and HCC development. Besides, HMGB1 regulated RAC1 aggregation to the cell membrane under hypoxia. Finally, the changes and significance of related molecules in clinical samples of HCC were analyzed using bioinformatics and tissue microarray analyses. We found that HCC patients with high HMGB1, RHOT1, or RAC1 expression exhibited a relatively shorter overall survival period. In conclusion, under hypoxic conditions, HMGB1 promoted mitochondrial transfer and migration and invasion of HCC cells by increasing the expression of mitochondrial transport protein RHOT1 and TNTs formation-related protein RAC1.

Identification of PANoptosis-Based Prognostic Signature for Predicting Efficacy of Immunotherapy and Chemotherapy in Hepatocellular Carcinoma.

Background: PANoptosis has been a research hotspot, but the role of PANoptosis in hepatocellular carcinoma (HCC) remains widely unknown. Drug resistance and low response rate are the main limitations of chemotherapy and immunotherapy in HCC. Thus, construction of a prognostic signature to predict prognosis and recognize ideal patients for corresponding chemotherapy and immunotherapy is necessary. Method: The mRNA expression data of HCC patients was collected from TCGA database. Through LASSO and Cox regression, we developed a prognostic signature based on PANoptosis-related genes. KM analysis and ROC curve were implemented to evaluate the prognostic efficacy of this signature, and ICGC and GEO database were used as external validation cohorts. The immune cell infiltration, immune status, and IC50 of chemotherapeutic drugs were compared among different risk subgroups. The relationships between the signature and the efficacy of ICI therapy, sorafenib treatment, and transcatheter arterial chemoembolization (TACE) therapy were investigated. Result: A 3-gene prognostic signature was constructed which divided the patients into low- and high-risk subgroups. Low-risk patients had better prognosis, and the risk score was proved to be an independent predictor of overall survival (OS), which had a well predictive effect. Patients in high-risk population had more immunosuppressive cells (Tregs, M0 macrophages, and MDSCs), higher TIDE score and TP53 mutation rate, and elevated activity of base excision repair (BER) pathways. Patients with low risk benefited more from ICI, TACE, and sorafenib therapy. The predictive value of the risk score was comparable with TIDE and MSI for OS under ICI therapy. The risk score could be a biomarker to predict the response to ICI, TACE, and sorafenib therapy. Conclusion: The novel signature based on PANoptosis is a promising biomarker to distinguish the prognosis predict the benefit of ICI, TACE, and sorafenib therapy, and forecast the response to them.

Pathophysiological role of BACH transcription factors in digestive system diseases.

BTB and CNC homologous (BACH) proteins, including BACH1 and BACH2, are transcription factors that are widely expressed in human tissues. BACH proteins form heterodimers with small musculoaponeurotic fibrosarcoma (MAF) proteins to suppress the transcription of target genes. Furthermore, BACH1 promotes the transcription of target genes. BACH proteins regulate physiological processes, such as the differentiation of B cells and T cells, mitochondrial function, and heme homeostasis as well as pathogenesis related to inflammation, oxidative-stress damage caused by drugs, toxicants, or infections; autoimmunity disorders; and cancer angiogenesis, epithelial-mesenchymal transition, chemotherapy resistance, progression, and metabolism. In this review, we discuss the function of BACH proteins in the digestive system, including the liver, gallbladder, esophagus, stomach, small and large intestines, and pancreas. BACH proteins directly target genes or indirectly regulate downstream molecules to promote or inhibit biological phenomena such as inflammation, tumor angiogenesis, and epithelial-mesenchymal transition. BACH proteins are also regulated by proteins, miRNAs, LncRNAs, labile iron, and positive and negative feedback. Additionally, we summarize a list of regulators targeting these proteins. Our review provides a reference for future studies on targeted drugs in digestive diseases.