LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

Infiltrative Vessel Co-optive Growth Pattern Induced by IQGAP3 Overexpression Promotes Microvascular Invasion in Hepatocellular Carcinoma.

PURPOSE: Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. EXPERIMENTAL DESIGN: The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. RESULTS: IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. CONCLUSIONS: Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.

Abscisic acid-induced transcription factor PsMYB306 negatively regulates tree peony bud dormancy release.

Bud dormancy is a crucial strategy for perennial plants to withstand adverse winter conditions. However, the regulatory mechanism of bud dormancy in tree peony (Paeonia suffruticosa) remains largely unknown. Here, we observed dramatically reduced and increased accumulation of abscisic acid (ABA) and bioactive gibberellins (GAs) GA1 and GA3, respectively, during bud endodormancy release of tree peony under prolonged chilling treatment. An Illumina RNA sequencing study was performed to identify potential genes involved in the bud endodormancy regulation in tree peony. Correlation matrix, principal component, and interaction network analyses identified a downregulated MYB transcription factor gene, PsMYB306, the expression of which positively correlated with 9-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (PsNCED3) expression. Protein modeling analysis revealed 4 residues within the R2R3 domain of PsMYB306 to possess DNA binding capability. Transcription of PsMYB306 was increased by ABA treatment. Overexpression of PsMYB306 in petunia (Petunia hybrida) inhibited seed germination and plant growth, concomitant with elevated ABA and decreased GA contents. Silencing of PsMYB306 accelerated cold-triggered tree peony bud burst and influenced the production of ABA and GAs and the expression of their biosynthetic genes. ABA application reduced bud dormancy release and transcription of ENT-KAURENOIC ACID OXIDASE 1 (PsKAO1), GA20-OXIDASE 1 (PsGA20ox1), and GA3-OXIDASE 1 (PsGA3ox1) associated with GA biosynthesis in PsMYB306-silenced buds. In vivo and in vitro binding assays confirmed that PsMYB306 specifically transactivated the promoter of PsNCED3. Silencing of PsNCED3 also promoted bud break and growth. Altogether, our findings suggest that PsMYB306 negatively modulates cold-induced bud endodormancy release by regulating ABA production.

CircMMP2(6,7) Cooperates with ß-Catenin and PRMT5 to Disrupt Bone Homeostasis and Promote Breast Cancer Bone Metastasis.

The bone is the most common site of distant metastasis of breast cancer, which leads to serious skeletal complications and mortality. Understanding the mechanisms underlying breast cancer bone metastasis would provide potential strategies for the prevention and treatment of breast cancer bone metastasis. In this study, we identified a circular RNA that we named circMMP2(6,7) that was significantly upregulated in bone metastatic breast cancer tissues and correlated with breast cancer-bone metastasis. Upregulation of circMMP2(6,7) dramatically enhanced the metastatic capability of breast cancer cells to the bone via inducing bone metastatic niche formation by disrupting bone homeostasis. Mechanistically, circMMP2(6,7) specifically bound to the promoters of bone-remodeling factors calcium-binding protein S100A4 and carbohydrate-binding protein LGALS3 and formed a complex with ß-catenin and arginine methyltransferase PRMT5, eliciting histone H3R2me1/H3R2me2s-induced transcriptional activation. Treatment with GSK591, a selective PRMT5 inhibitor, effectively inhibited circMMP2(6,7)/ß-catenin/PRMT5 complex-induced breast cancer bone metastasis. These findings reveal a role for circMMP2(6,7) in bone homeostasis disruption and shed light on the mechanisms driving breast cancer bone metastasis. SIGNIFICANCE: Upregulation of bone-remodeling factors S100A4 and LGALS3 mediated by a circMMP2(6,7)/ß-catenin/PRMT5 complex generates a niche that supports breast cancer bone metastasis, identifying PRMT5 as a promising target for treating metastasis.

Downregulation of BASP1 Promotes Temozolomide Resistance in Gliomas via Epigenetic Activation of the FBXO32/NF-κB/MGMT Axis.

The chemoresistance of temozolomide-based therapy is a serious limitation for lasting effective treatment of gliomas, while the underlying mechanisms remain unclear. In this study, we showed that downregulation of BASP1 correlated negatively with the response to temozolomide therapy and disease-free survival (DFS) of patients with gliomas. Silencing BASP1 significantly enhanced the temozolomide resistance of glioma cells both in vitro and in vivo through repair of temozolomide-induced DNA damage via activation of the FBXO32/NF-κB/MGMT axis in both MGMT-methylated and -unmethylated gliomas. We demonstrated that loss of BASP1 resulted in removal of TRIM37/EZH2 complex-induced repressive histone modifications, including H2A-ub and H3K27me3, but addition of WDR5/MLL complex-mediated active histone modifications, including H3K4me3 and H3K9ac, on the FBXO32 promoter, which elicited in FBXO32 upregulation and further activated NF-κB/MGMT signaling via ubiquitin-dependent degradation of IκBα. Importantly, treatment with OICR-9429, an antagonist of the WDR5-MLL interaction, impaired the FBXO32/NF-κB/MGMT axis-mediated repair of temozolomide-induced DNA damage, leading to significant apoptosis of BASP1-downregulated glioma cells. These findings shed light on the molecular mechanism underlying BASP1-mediated epigenetic transcriptional repression and may represent a potential strategy in the fight against temozolomide-resistant gliomas. IMPLICATIONS: BASP1 downregulation promotes temozolomide resistance in gliomas through WDR5/MLL complex-mediated epigenetic activation of the FBXO32/NF-κB/MGMT axis, providing new target for improving outcomes in patients with temozolomide-resistant gliomas.

SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma.

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.

Efficacy and safety of tailin formulation combined with continuous low-dose antibiotic therapy in patients with recurrent urinary tract infection: A multicenter, randomized, controlled clinical trial.

Persistent inflammation associated with recurrent urinary tract infection (rUTI) is a crucial inducement of inflammation-driven renal fibrosis (IDRF). Although continuous low-dose antibiotic therapy (CLAT) is the common treatment for rUTI, its clinical efficacy remains unsatisfactory. Tailin formulation (TLF), a Chinese herbal formulation prescribed for treating rUTI, is effective in alleviating symptoms and reducing recurrence. This study was to evaluate the efficacy and safety of TLF combined with CLAT compared with CLAT used alone in patients with rUTI. In this multicenter, randomized, controlled clinical trial, patients were assigned (1:1) to receive either TLF + CLAT or CLAT for 12 weeks. The primary outcome was the effective rate at week 12 of the treatment. The secondary outcomes were the recurrent rate at week 4 and week 12 post treatment; the post-treatment changes in renal tubular injury markers (urinary N-acetyl-ß-d-glucosaminidase (NAG) and ß2-microglobulin (ß2-MG)), profibrotic factors (urinary monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor beta1 (TGF-ß1)), and traditional Chinese medicine (TCM) symptoms, and vital signs indicators and serious adverse events (SAEs) were also monitored throughout the trial. A total of 195 patients were included in the final analysis. The TLF + CLAT group had a higher effective rate and a lower recurrence rate than the CLAT group (p < 0.01). Significant decrease of urinary NAG and ß2-MG was observed in the TLF + CLAT group vs. CLAT group (p < 0.01), and similar changes were observed in profibrotic factors (urinary MCP-1 and TGF-ß1) (p < 0.05), which indicated that TLF might have potential renal tubular protection and anti-fibrosis effects. Additionally, a positive correlation within a certain range was shown in the correlation analysis of medical history (months) of rUTI patients with urinary MCP-1 (r = 0.50, p < 0.05) and TGF-ß1 (r = 0.78, p < 0.01). A significant difference was also observed in TCM symptoms (p < 0.01). There were no obvious adverse reactions that occurred during this study. We conclude that TLF combined with CLAT was superior to CLAT used alone in reducing rUTI recurrence, alleviating the non-infection-related physical symptoms and protecting renal tubular and anti-fibrosis, which suggests this novel therapy might be an available treatment with great promise in treating rUTI.

Large Oncosome-Loaded VAPA Promotes Bone-Tropic Metastasis of Hepatocellular Carcinoma Via Formation of Osteoclastic Pre-Metastatic Niche.

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott-Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.

LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.

NKX2-8/PTHrP Axis-Mediated Osteoclastogenesis and Bone Metastasis in Breast Cancer.

Bone metastasis is one of the most common distant metastasis of breast cancer, which could cause serious skeletal disease and increased cancer-related death. Therefore, identification of novel target(s) to develop therapeutics would improve patient outcomes. The role of NKX2-8 in modulation of bone remodeling was determined using osteoclastogenesis and micro-CT assays. The expression of NKX2-8 was examined via immunohistochemistry analysis in 344 breast cancer tissues. The mechanism underlying NKX2-8-mediated PTHrP downregulation was investigated using biotinylated deactivated Cas9 capture analysis, chromatin immunoprecipitation, co-immunoprecipitation assays. A bone-metastatic mouse model was used to examine the effect of NKX2-8 dysregulation on breast cancer bone metastasis and the impact of three PTHrP inhibitor on prevention of breast cancer bone metastasis. The downregulated expression of NKX2-8 was significantly correlated with breast cancer bone metastasis. In vivo bone-metastatic mouse model indicated that silencing NKX2-8 promoted, but overexpressing NKX2-8 inhibited, breast cancer osteolytic bone metastasis and osteoclastogenesis. Mechanistically, NKX2-8 directly interacted with HDAC1 on the PTHrP promoter, which resulted in a reduction of histone H3K27 acetylation, consequently transcriptionally downregulated PTHrP expression in breast cancer cells. Furthermore, targeting PTHrP effectively inhibited NKX2-8-downregulation-mediated breast cancer bone metastasis. Taken together, our results uncover a novel mechanism underlying NKX2-8 downregulation-mediated breast cancer bone metastasis and represent that the targeting PTHrP might be a tailored treatment for NKX2-8 silencing-induced breast cancer bone metastasis.

Integrated Analysis of Glutathione Metabolic Pathway in Pancreatic Cancer.

Metabolic enzyme-genes (MEs) play critical roles in various types of cancers. However, MEs have not been systematically and thoroughly studied in pancreatic cancer (PC). Global analysis of MEs in PC will help us to understand PC progressing and provide new insights into PC therapy. In this study, we systematically analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) (n = 180 + 4) and GSE15471 (n = 36 + 36) and discovered that metabolic pathways are disordered in PC. Co-expression network modules of MEs were constructed using weighted gene co-expression network analysis (WGCNA), which identified two key modules. Both modules revealed that the glutathione signaling pathway is disordered in PC and correlated with PC stages. Notably, glutathione peroxidase 2 (GPX2), an important gene involved in glutathione signaling pathway, is a hub gene of the key modules. Analysis of immune microenvironment components reveals that PC stage is associated with M2 macrophages, the marker gene of which is significantly correlated with GPX2. The results indicated that GPX2 is associated with PC progression, providing new insights for future targeted therapy.

Transcriptome Profiling Reveals a Petunia Transcription Factor, PhCOL4, Contributing to Antiviral RNA Silencing.

RNA silencing is a common antiviral mechanism in eukaryotic organisms. However, the transcriptional regulatory mechanism that controls the RNA silencing process remains elusive. Here, we performed high-depth transcriptome analysis on petunia (Petunia hybrida) leaves infected with tobacco rattle virus (TRV) strain PPK20. A total of 7,402 differentially expressed genes (DEGs) were identified. Of them, some RNA silencing-related transcripts, such as RNA-dependent RNA polymerases (RDRs), Dicer-like RNase III enzymes (DCLs), and Argonautes (AGOs), were induced by viral attack. Furthermore, we performed TRV-based virus-induced gene silencing (VIGS) assay on 39 DEGs encoding putative transcription factors (TFs), using green fluorescent protein (GFP) and phytoene desaturase (PhPDS) as reporters. Results showed that the down-regulation of PhbHLH41, PhbHLH93, PhZPT4-3, PhCOL4, PhHSF-B3A, PhNAC90, and PhWRKY75 led to enhanced TRV accumulation and inhibited PhPDS-silenced photobleaching phenotype. In contrast, silencing of PhERF22 repressed virus accumulation and promoted photobleaching development. Thus, these TFs were identified as potential positive and negative regulators of antiviral RNA silencing, respectively. One positive regulator PhCOL4, belonging to the B-box zinc finger family, was selected for further functional characterization. Silencing and transient overexpression of PhCOL4 resulted in decreased and increased expression of several RNA silencing-related genes. DNA affinity purification sequencing analysis revealed that PhCOL4 targeted PhRDR6 and PhAGO4. Dual luciferase and yeast one-hybrid assays determined the binding of PhCOL4 to the PhRDR6 and PhAGO4 promoters. Our findings suggest that TRV-GFP-PhPDS-based VIGS could be helpful to identify transcriptional regulators of antiviral RNA silencing.

Properties and digestibility of a novel porous starch from lotus seed prepared via synergistic enzymatic treatment.

The objective was to investigate the effect of synergistic enzymatic treatment on the properties and digestibility of a novel C-type lotus seed porous starch (LPS). Scanning electron microscopy showed that the densest and most complete pores were formed on the surface of LPS when the concentration of enzymes added was 1.5% (LS-1.5E). With increases in enzyme addition, the oil and water absorption of the porous starch increased and reached maxima at 1.5% of enzyme. Increased in the specific surface area, total pore volume and average pore diameter of LPS were determined by low-temperature nitrogen adsorption, while when the enzymes exceeded 1.5%, there were no significant changes. Compared to lotus seed starch (LS), the particle size of LPS also decreased. With the increases in enzyme addition, LPS exhibited higher relative crystallinity and ordering structure by XRD and FTIR. The results by SAXS confirmed that LPS had higher ordered semi-crystalline lamellar and denser lamellar structure compared to LS. Low-field 1H NMR spectroscopy indicated that the proportion of bound water in LPS increased, while the proportion of bulk water decreased. Moreover, the degree of hydrolysis of LPS was lower than that of LS, and the content of rapidly digestible starch decreased, while the content of slowly digestible starch and resistant starch increased with the enzyme addition, which was consistent with the structural properties.

Clinical efficacy of Tailin formulation combined with continuous low-dose antimicrobial therapy for recurrent urinary tract infection: study protocol for a multicenter, double-blind, randomized, controlled clinical trial.

BACKGROUND: Given the increasing rates of antimicrobial resistance (AMR), recurrent urinary tract infection (rUTI) is becoming refractory more and more. Antibiotic prophylaxis including continuous low-dose antibiotic therapy (CLAT), is the common treatment for rUTI of the world. However, the presumably adverse reactions caused by CLAT alone should be paid more attention. Studies indicated that Chinese herbal medicine (CHM) might be an available treatment method for rUTI. Tailin formulation (TLF) is a herbal prescription developed for the treatment of rUTI in the 2000s in Shanghai Municipal Hospital of Traditional Chinese Medicine. Our previous studies have shown TLF could prevent urinary tract infection both in pyelonephritis (PN) rat model and in PN patients. Additionally, our published data demonstrated TLF is helpful to reduce the recurrence of rUTI and protect renal tubular function in clinic. In order to find a novel treating project for rUTI to increase the clinical curative effect, we thus try to combine TLF with CLAT to treat rUTI and design an optimized, pragmatically clinical trial to evaluate the efficacy and safety of this project. METHODS/DESIGN: This is a multicenter, double-blind, randomized, controlled clinical trial. We will enroll 200 eligible patients diagnosed with uncomplicated rUTI and then divide them randomly into two groups with a 1:1 ratio: TLF + CLAT group and placebo + CLAT group. This trial consists of two stages, a 12-week period of treatment and a 12-week period of post-treatment follow-up, respectively. The primary outcome will be the recurrence rate at the 12th week of the follow-up period; the second outcomes will be the post-treatment changes in renal and liver function; furthermore, traditional Chinese medicine (TCM) symptoms, non-infection-related physical signs, and subjective symptoms will be scored, and the number of episodes of each subject will be also recorded; meanwhile, vital signs indicators and serious adverse events (SAEs) will be monitored throughout the trial. DISCUSSION: This study will provide convictive research-derived data to evaluate clinical efficacy and safety of TLF combined with CLAT for rUTI, and provide an evidence-based recommendation for clinicians. Moreover, post-treatment changes in non-infection-related physical signs and subjective symptoms were included in the efficacy evaluation, which is important and more significant for assessing the clinical benefits for those rUTI patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2100041914 . Registered on 10 January 2021. Protocol date and version: September 12, 2020; version 1.

Circular RNA circIKBKB promotes breast cancer bone metastasis through sustaining NF-κB/bone remodeling factors signaling.

BACKGROUND: Breast cancer (BC) has a marked tendency to spread to the bone, resulting in significant skeletal complications and mortality. Recently, circular RNAs (circRNAs) have been reported to contribute to cancer initiation and progression. However, the function and mechanism of circRNAs in BC bone metastasis (BC-BM) remain largely unknown. METHODS: Bone-metastatic circRNAs were screened using circRNAs deep sequencing and validated using in situ hybridization in BC tissues with or without bone metastasis. The role of circIKBKB in inducing bone pre-metastatic niche formation and bone metastasis was determined using osteoclastogenesis, immunofluorescence and bone resorption pit assays. The mechanism underlying circIKBKB-mediated activation of NF-κB/bone remodeling factors signaling and EIF4A3-induced circIKBKB were investigated using RNA pull-down, luciferase reporter, chromatin isolation by RNA purification and enzyme-linked immunosorbent assays. RESULTS: We identified that a novel circRNA, circIKBKB, was upregulated significantly in bone-metastatic BC tissues. Overexpressing circIKBKB enhanced the capability of BC cells to induce formation of bone pre-metastatic niche dramatically by promoting osteoclastogenesis in vivo and in vitro. Mechanically, circIKBKB activated NF-κB pathway via promoting IKKß-mediated IκBα phosphorylation, inhibiting IκBα feedback loop and facilitating NF-κB to the promoters of multiple bone remodeling factors. Moreover, EIF4A3, acted acting as a pre-mRNA splicing factor, promoted cyclization of circIKBKB by directly binding to the circIKBKB flanking region. Importantly, treatment with inhibitor eIF4A3-IN-2 reduced circIKBKB expression and inhibited breast cancer bone metastasis effectively. CONCLUSION: We revealed a plausible mechanism for circIKBKB-mediated NF-κB hyperactivation in bone-metastatic BC, which might represent a potential strategy to treat breast cancer bone metastasis.

Epigenetic Induction of Mitochondrial Fission Is Required for Maintenance of Liver Cancer-Initiating Cells.

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.

RNF219/α-Catenin/LGALS3 Axis Promotes Hepatocellular Carcinoma Bone Metastasis and Associated Skeletal Complications.

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

Large exchange bias and enhanced coercivity in strongly-coupled Ni/NiO binary nanoparticles.

In this study, Ni/NiO binary nanoparticles are synthesized utilizing a reflux method combined with a calcination process. The average size of the nanoparticles is 5-20 nm and the Ni content is 3.55%. Both the microstructures of the Ni/NiO interface and the states of different phases have significant impacts on the magnetic properties. By tuning the temperature and the cooling field during the loop measurement, the change rule of several critical parameters such as coercivity H C and exchange bias H E was complicated in nature. Both large H E (482 Oe) and enhanced H C (1335 Oe) were observed at 5 K, mainly due to the strong coupling interaction between Ni and NiO components. For current studies of the Ni/NiO binary nanoparticles, the complex magnetic behaviors are related to (i) the ferromagnetic contribution of Ni nanoparticles, (ii) the intrinsic antiferromagnetism of the volume phase of NiO, and (iii) the spin-glass-like characteristic corresponding to the frozen disordered state at the surface of partial NiO particles. The comprehensive effect of these three magnetic structures promotes the generation of a strongly-coupled Ni/NiO binary system, and improves the magnetic performance.