RBMS3-loss impedes TRIM21-induced ubiquitination of ANGPT2 in an RNA-independent manner and drives sorafenib resistance in hepatocellular carcinoma
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Circulating mitochondrial DNA promotes M2 polarization of tumor associated macrophages and HCC resistance to sorafenib
Mitochondrial damage-associated molecular patterns (DAMPs) including mitochondrial DNA (mtDNA), TFAM (transcription factor A, mitochondrial), and ATP, which play crucial roles in the regulation of inflammatory environment in human diseases. However, the role of mitochondrial DAMPs in regulating tumor microenvironment (TME) remains unclear. Herein, we demonstrate that infiltration of M2-type tumor-associated macrophages (TAMs) was correlated with the resistance of hepatocellular carcinoma (HCC) to sorafenib. We found that cell-free mtDNA in the plasma was significantly increased in sorafenib-resistant HCC mice. Sorafenib induced mitochondrial dysfunction and promoted the release of mtDNA into extracellular matrix of HCC. Macrophages retook the mtDNA in the TME of HCC, activated TLR9 signaling, and promoted the activation of NF-κB and the polarization of TAMs into M2. Application of DNase I to digest mtDNA or depletion of macrophages with clodronate liposomes reduced M2 macrophage infiltration, decreased the growth of HCC, and sensitized the tumors to sorafenib. Furthermore, we showed that blocking the activation of TLR9 enhanced the therapeutic effect of sorafenib in HCC. Together, we demonstrate that sorafenib treatment leads to the release of mtDNA into TME in HCC, which in turn facilitates the polarization of TAMs into M2 macrophages through TLR9 activation and aggravates the resistance of HCC to sorafenib. Our study reveals a novel mechanism underlying circulating mtDAMPs in remodeling the HCC microenvironment by reprograming the TAMs and provides a new strategy for improving the therapeutic effect of sorafenib and overcoming its resistance in HCC.
TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma
Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1’s essential role in liver CSCs’ function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1’s active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1’s pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Ubiquitin and ubiquitin-like proteins in HPV-driven carcinogenesis
Persistent infection with high-risk (HR) human papillomaviruses (HPVs) is responsible for approximately 5% of cancer cases worldwide, including a growing number of oropharyngeal and anogenital cancers. The major HPV oncoproteins, E6 and E7, act together to manipulate cellular pathways involved in the regulation of proliferation, the cell cycle and cell survival, ultimately driving malignant transformation. Protein ubiquitination and the ubiquitin proteasome system (UPS) is often deregulated upon viral infection and in oncogenesis. HPV E6 and E7 interact with and disrupt multiple components of the ubiquitination machinery to promote viral persistence, which can also result in cellular transformation and the formation of tumours. This review highlights the ways in which HPV manipulates protein ubiquitination and the ubiquitin-like protein pathways and how this contributes to tumour development. Furthermore, we discuss how understanding the interactions between HPV and the protein ubiquitination could lead to novel therapeutic targets that are of urgent need in HPV+ carcinomas.
Complement activation in tumor microenvironment after neoadjuvant therapy and its impact on pancreatic cancer outcomes
Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC). This study investigates how NAT differentially impacts PDAC’s carcinoma cells and the tumor microenvironment (TME). Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME of 23 NAT-treated versus 13 NAT-naïve PDACs. Findings were validated by single-nucleus RNA sequencing (snRNA-seq) analysis. NAT induces apoptosis and inhibits proliferation of carcinoma cells and coordinately upregulates multiple complement genes (C1R, C1S, C3, C4B and C7) within the TME. Higher TME complement expression following NAT is associated with increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells; reduced immune exhaustion gene expression, and improved overall survival. snRNA-seq analysis demonstrates C3 complement is mainly upregulated in CAFs. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response, and guiding therapeutic strategies in NAT-treated PDAC patients.
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