HIF1A-dependent overexpression of MTFP1 promotes lung squamous cell carcinoma development by activating the glycolysis pathway.

Introduction: Mitochondrial fission process 1 (MTFP1) is an inner mitochondrial membrane (IMM) protein implicated in the development and progression of various tumors, particularly lung squamous cell carcinoma (LUSC). This study aims to provide a more theoretical basis for the treatment of LUSC. Methods: Through bioinformatics analysis, MTFP1 was identified as a novel target gene of HIF1A. MTFP1 expression in LUSC was examined using The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Proteomics Data Commons (PDC) databases. The Kaplan-Meier plotter (KM plotter) database was utilized to evaluate its correlation with patient survival. Western blot and chromatin immunoprecipitation (ChIP) assays were employed to confirm the regulatory relationship between MTFP1 and HIF1A. Additionally, cell proliferation, colony formation, and migration assays were conducted to investigate the mechanism by which MTFP1 enhances LUSC cell proliferation and metastasis. Results: Our findings revealed that MTFP1 overexpression correlated with poor prognosis in LUSC patients(P < 0.05). Moreover, MTFP1 was closely associated with hypoxia and glycolysis in LUSC (R = 0.203; P < 0.001, R = 0.391; P < 0.001). HIF1A was identified as a positive regulator of MTFP1. Functional enrichment analysis demonstrated that MTFP1 played a role in controlling LUSC cell proliferation. Cell proliferation, colony formation, and migration assays indicated that MTFP1 promoted LUSC cell proliferation and metastasis by activating the glycolytic pathway (P < 0.05). Conclusions: This study establishes MTFP1 as a novel HIF1A target gene that promotes LUSC growth by activating the glycolytic pathway. Investigating MTFP1 may contribute to the development of effective therapies for LUSC patients, particularly those lacking targeted oncogene therapies.

FOXP4-mediated induction of PTK7 activates the Wnt/ß-catenin pathway and promotes ovarian cancer development.

Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4's function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

FBXO5-mediated RNF183 degradation prevents endoplasmic reticulum stress-induced apoptosis and promotes colon cancer progression.

Endoplasmic reticulum (ER) stress induces the unfolded protein response (UPR), and prolonged ER stress leads to cell apoptosis. Despite increasing research in this area, the underlying molecular mechanisms remain unclear. Here, we discover that ER stress upregulates the UPR signaling pathway while downregulating E2F target gene expression and inhibiting the G2/M phase transition. Prolonged ER stress decreases the mRNA levels of E2F2, which specifically regulates the expression of F-Box Protein 5(FBXO5), an F-box protein that functions as an inhibitor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex. Depletion of FBXO5 results in increased ER stress-induced apoptosis and decreased expression of proteins related to PERK/IRE1α/ATF6 signaling. Overexpression of FBXO5 wild-type (not its ΔF-box mutant) alleviates apoptosis and the expression of the C/EBP Homologous Protein (CHOP)/ATF. Mechanistically, we find that FBXO5 directly binds to and promotes the ubiquitin-dependent degradation of RNF183, which acts as a ubiquitin E3 ligase in regulating ER stress-induced apoptosis. Reversal of the apoptosis defects caused by FBXO5 deficiency in colorectal cancer cells can be achieved by knocking down RNF183 in FBXO5-deficient cells. Functionally, we observed significant upregulation of FBXO5 in colon cancer tissues, and its silencing suppresses tumor occurrence in vivo. Therefore, our study highlights the critical role of the FBXO5/RNF183 axis in ER stress regulation and identifies a potential therapeutic target for colon cancer treatment.

Self-Cross-Linked Chitosan/Albumin-Bound Nanoparticle Hydrogel for Inhibition of Postsurgery Malignant Glioma Recurrence.

The development of chemoimmunotherapy with reduced systemic toxicity using local formulations is an effective strategy for combating tumor recurrence. Herein, we reported a localized hydrogel system for antitumor chemoimmunotherapy, formed by doxorubicin (DXR)-loaded bovine serum albumin (BSA) nanoparticles self-cross-linked with natural polysaccharide chitosan (CS). The drug-loaded hydrogel (DXR-CBGel) with antiswelling performance and prolonged drug-release profile was combined with antiprogrammed cell death protein 1 (aPD-1) as an in situ vaccine for treating glioblastoma multiforme (GBM) lesions. The antiswelling hydrogel system shows excellent biosafety for volume-sensitive GBM lesions. Both the albumin-bound formulation and the in situ gelation design facilitate the local retention and sustained release of DXR to generate long-term chemoimmunotherapy with reduced systemic toxicity. The chemotherapy-induced immunogenic cell death of DXR with the assistance of immunotherapeutic CS can trigger tumor-specific immune responses, which are further amplified by an immune checkpoint blockade to effectively inhibit cancer recurrence. The strategy of combining albumin-bound drug formulation and biocompatible polymer-based hydrogel for localized chemoimmunotherapy shows great potential against postsurgery glioblastoma recurrence.

USP14 regulates heme metabolism and ovarian cancer invasion through BACH1 deubiquitination and stabilization.

The deubiquitinating enzyme USP14 has been established as a crucial regulator in various diseases, including tumors, neurodegenerative diseases, and metabolic diseases, through its ability to stabilize its substrate proteins. Our group has utilized proteomic techniques to identify new potential substrate proteins for USP14, however, the underlying signaling pathways regulated by USP14 remain largely unknown. Here, we demonstrate the key role of USP14 in both heme metabolism and tumor invasion by stabilizing the protein BACH1. The cellular oxidative stress response factor NRF2 regulates antioxidant protein expression through binding to the antioxidant response element (ARE). BACH1 can compete with NRF2 for ARE binding, leading to the inhibition of the expression of antioxidant genes, including HMOX-1. Activated NRF2 also inhibits the degradation of BACH1, promoting cancer cell invasion and metastasis. Our findings showed a positive correlation between USP14 expression and NRF2 expression in various cancer tissues from the TCGA database and normal tissues from the GTEx database. Furthermore, activated NRF2 was found to increase USP14 expression in ovarian cancer (OV) cells. The overexpression of USP14 was observed to inhibit HMOX1 expression, while USP14 knockdown had the opposite effect, suggesting a role for USP14 in regulating heme metabolism. The depletion of BACH1 or inhibition of heme oxygenase 1 (coded by HMOX-1) was also found to significantly impair USP14-dependent OV cell invasion. In conclusion, our results highlight the importance of the NRF2-USP14-BACH1 axis in regulating OV cell invasion and heme metabolism, providing evidence for its potential as a therapeutic target in related diseases.

Multifunctional theragnostic ultrasmall gold nanodot-encapsuled perfluorocarbon nanodroplets for laser-focused ultrasound sequence irradiation (LFSI)-based enhanced tumor ablation.

Despite the substantial potential of focused ultrasound therapy, its efficacy in cancer therapy has been limited due to the high cavitation threshold and safety concerns regarding the use of high-intensity energy pulses. Here, ultrasmall Au nanodot-loaded PEG-modified perfluorocarbon nanodroplets (Au-PFCnDs) were prepared and used as a therapeutic enhancer. A LFSI method was designed to achieve enhanced tumor ablation at a mild focused ultrasound (FUS) energy pulse with the assistance of the instinct photothermal effect of intratumor-permeable ultrasmall Au nanodots under 808 nm NIR laser irradiation. In addition to their therapeutic function, Au-PFCnDs can also generate multimodal images to provide information for tumor surveillance and treatment guidance. The experimental results also showed that the cRGD-targeted Au-PFCnDs could be more efficiently delivered into the tumor and selectively destroy tumors with no observable side effects on normal tissue under LFSI treatment.

ZeMYB9 regulates cyanidin synthesis by activating the expression of flavonoid 3'-hydroxylase gene in Zinnia elegans.

Petal color in Zinnia elegans is characterized mainly by anthocyanin accumulation. The difference in the content of anthocyanins, especially cyanidins, affects petal coloration in Z. elegans, but the underlying regulatory mechanism remains elusive. Here, we report one R2R3-MYB transcription factor from subgroup 6, ZeMYB9, acting as a positive regulator of anthocyanin accumulation in Z. elegans. Up-regulated expression of ZeMYB9 and flavonoid 3'-hydroxylase gene (ZeF3'H) was detected in the cultivar with higher cyanidin content. ZeMYB9 could specifically activate the promoter of ZeF3'H, and over-expression of ZeMYB9 induces much greater anthocyanin accumulation and higher expression level of anthocyanin biosynthetic genes in both petunia and tobacco. And then, ZeMYB9 was demonstrated to interact with ZeGL3, a bHLH transcription factor belonging to IIIf subgroup. Promoter activity of ZeF3'H was significantly promoted by co-expressing ZeMYB9 and ZeGL3 compared with expressing ZeMYB9 alone. Moreover, transient co-expression of ZeMYB9 and ZeGL3 induced anthocyanin accumulation in tobacco leaves. Our results suggest that ZeMYB9 could enhance cyanidin synthesis and regulate petal color in Z. elegans though activating the expression of ZeF3'H, by itself or interacting with ZeGL3.

Transforming Passive into Active: Multimodal Pheophytin-Based Carbon Dots Customize Protein Corona to Target Metastatic Breast Cancer.

Formation of protein corona on nanomaterials surface in vivo is usually considered as an unpredictable event for a predefined targeted delivery system for malignant cancers. In most situations, these protein coronas substantially change targeting efficiency or even cause adverse reactions which both hinder the clinical translation of the cargo-delivery systems. Active customization of protein corona onto nanomaterials surfaces can benefit their biomedical performances and open up new opportunities in construction of targeted delivery systems. Herein, lipid-PEG/pheophytin carbon dots (LPCDs) are prepared from natural chlorophyll and integrate seamlessly with positron emission tomography imaging, near-infrared fluorescence imaging, and photodynamic therapy capacity. In vitro measurements demonstrate that the LPCDs can actively absorb apolipoproteins into the protein corona to enhance their uptakes in breast cancer cells. In vivo studies confirm that LPCDs can give accurate delineation of metastatic breast cancer foci from surrounding normal tissues with multimodal biomedical functions. The feasibility of using LPCDs as a multimodal imaging and cancer-targeting nanoplatform may provide impetus for developing precise yet facile protein corona-targeted delivery systems for future clinical practice.

In vitro immunomodulation of magnesium on monocytic cell toward anti-inflammatory macrophages.

Biodegradable magnesium (Mg) has shown great potential advantages over current bone fixation devices and vascular scaffold technologies; however, there are few reports on the immunomodulation of corrosive Mg products, the micron-sized Mg particles (MgMPs). Human monocytic leukemia cell line THP-1 was set as the in vitro cell model to estimate the immunomodulation of MgMPs on cell proliferation, apoptosis, polarization and inflammatory reaction. Our results indicated high-concentration of Mg2+ demoted the proliferation of the THP-1 cells and, especially, THP-1-derived macrophages, which was a potential factor that could affect cell function, but meanwhile, cell apoptosis was almost not affected by Mg2+. In particular, the inflammation regulatory effects of MgMPs were investigated. Macrophages exposed to Mg2+ exhibited down-regulated expressions of M1 subtype markers and secretions of pro-inflammatory cytokines, up-regulated expression of M2 subtype marker and secretion of anti-inflammatory cytokine. These results indicated Mg2+ could convert macrophages from M0 to M2 phenotype, and the bioeffects of MgMPs on human inflammatory cells were most likely due to the Mg2+-induced NF-κB activation reduction. Together, our results proved Mg2+ could be used as a new anti-inflammatory agent to suppress inflammation in clinical applications, which may provide new ideas for studying the immunomodulation of Mg-based implants on human immune system.