Nude Mouse Model Research Articles

SLC38A5 suppresses ferroptosis through glutamine-mediated activation of the PI3K/AKT/mTOR signaling in osteosarcoma

BackgroundSolute carrier family 38 member 5 (SLC38A5) is an amino acid transporter that plays a significant role in various cellular biological processes and may be involved in regulating the progression of tumors However, its function and underlying mechanism in osteosarcoma remain unexplored.MethodsUtilizing various database analyses and experiments, we have explored the dysregulation of SLC38A5 in osteosarcoma and its prognostic value. A series of in vitro functional experiments, including CCK-8, colony formation, wound healing, and transwell invasion assays, were conducted to evaluate the effects of SLC38A5 on the proliferation, migration, and invasion of osteosarcoma cells. Downstream pathways of SLC38A5 were explored through methods such as western blot and metabolic assays, followed by a series of validations. Finally, we constructed a subcutaneous xenograft tumor model in nude mice to explore SLC38A5 function in vivo.ResultsSLC38A5 is upregulated in osteosarcoma and is associated with poor prognosis in patients. Upregulation of SLC38A5 promotes proliferation, migration, and invasion of osteosarcoma cells, while the PI3K inhibitor BKM120 can counteract these effects. Additionally, silencing of SLC38A5 inhibits tumor growth in vivo. Mechanistically, SLC38A5 mediates the activation of the PI3K/AKT/mTOR signaling pathway by transporting glutamine, which subsequently enhances the SREBP1/SCD-1 signaling pathway, thereby suppressing ferroptosis in osteosarcoma cells.ConclusionSLC38A5 promotes osteosarcoma cell proliferation, migration, and invasion via the glutamine-mediated PI3K/AKT/mTOR signaling pathway and inhibits ferroptosis. Targeting SLC38A5 and the PI3K/AKT signaling axis may provide a meaningful therapeutic strategy for the future treatment of osteosarcoma.Graphical abstracts

FGF6 inhibits oral squamous cell carcinoma progression by regulating PI3K/AKT and MAPK pathways

To explore diagnostic and prognostic biomarkers in the progression of oral squamous cell carcinoma (OSCC) and to reveal their regulatory mechanisms in key pathways. A RayBiotech protein chip was used to screen differentially expressed serum proteins in OSCC, oral leukoplakia (OLK), and healthy participants. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to determine the pathways enriched by characteristic differential proteins. Immunohistochemical analysis and western blotting were used to verify the expression of characteristic differential proteins and key regulatory factors in human tissues and in a nude mouse model. Fibroblast growth factor 6 (FGF6) was identified as a key differential protein and was weakly expressed in OSCC tissues. The mitogen-activated protein kinases (MAPK) and PI3K-AKT pathways were identified as key signaling pathways. The results showed that pERK, Cyclin D1, pAKT, and BCL2 were highly expressed in OSCC, Caspase9 was lowly expressed in OSCC. With an increase in FGF6 expression in nude mice, the expression of FGFR4, pERK, Cyclin D1, pAKT, BCL2, GPX4, and ACSL4 increased, and the expression of Caspase9 decreased. FGF6 may change the expression of apoptosis-related proteins and proliferation factors by binding to FGFR4 in the PI3K-AKT/MAPK pathway and may inhibit the ferroptosis of OSCC, thereby possibly participating in the process of inhibiting OSCC.

FNDC5 affects invasion and migration of oral cancer by inhibiting PI3K/Akt/Snail signaling pathway

This study first investigated how FNDC5 affected the development of oral cancer and revealed the role of FNDC5 in the migration and invasion of oral cancer. The present work evaluated differential FNDC5 expression within oral cancer samples versus matched non-carcinoma samples based on GEO database analysis and immunohistochemistry. We then generated oral cancer cell lines with FNDC5 overexpression and knockdown to determine the role of altered FNDC5 expression in the migration and invasion of oral cancer. PI3K inhibitor was used for investigating the possible mechanism underlying FNDC5 during EMT of oral cancer. Finally, these in-vitro results were validated using the lung metastatic nude mouse model. According to our results, FNDC5 level markedly decreased within oral cancer compared with adjacent samples and FNDC5 overexpression inhibited migration, invasion as well as EMT of oral cancer, while FNDC5 knockdown promoted oral cancer cell EMT. In addition, PI3K inhibitors blocked the induction of oral cancer cells EMT by FNDC5 knockdown. In vivo experiments further demonstrated the above results. This work is the first to illustrate the impact of FNDC5 on inhibiting migration and invasion of oral cancer, and our results suggest that FNDC5 affects EMT of oral cancer via the inhibition of PI3K/Akt/Snail pathway.

ST2L promotes VEGFA-mediated angiogenesis in gastric cancer by activating TRAF6/PI3K/Akt/NF-κB pathway via IL-33

Suppression of Tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor/ Toll-like receptor superfamily, and its specific ligand is Interleukin-33 (IL-33). IL-33/ ST2 signaling has been implicated in numerous inflammatory and allergic diseases, as well as in promoting malignant behavior of tumor cells and angiogenesis. However, the precise role of ST2 in gastric cancer angiogenesis remains incompletely elucidated. We observed a significant correlation between high expression of ST2 in gastric cancer tissues and poor prognosis, along with various clinicopathological features. In vitro experiments demonstrated that the IL-33/ ST2 axis activates the PI3K/AKT/NF-κB signaling pathway through TRAF6, thereby promoting VEGFA-mediated tumor angiogenesis; meanwhile sST2 acts as a decoy receptor to regulate the IL-33/ST2L axis. Consistent findings were also observed in subcutaneous xenograft tumor models in nude mice. Furthermore, we investigated the molecular mechanism by which IL-33 promotes ST2L expression in GC cells via upregulation of transcription factors YY1 and GATA2 through intracellular signaling pathways.

Mechanism of CXCL8 regulation of methionine metabolism to promote angiogenesis in gliomas

BackgroundGliomas are the most common malignant brain tumors characterized by angiogenesis and invasive growth. A detailed understanding of its molecular characteristics could provide potential therapeutic targets. In the present study, we sought to explore the key gene CXCL8 in methionine metabolism in gliomas and its potential role in angiogenesis.MethodsU251 glioma cells were divided into control and methionine-restriction tolerant (constructed with 1/4 of the standard level of methionine in the culture medium) groups for transcriptome and metabolome analysis. To confirm the functions and mechanism of CXCL8 in glioma, heat map, volcano map, Go enrichment, gene set enrichment analysis (GSEA), protein–protein interaction network analysis, RT-PCR, western blotting assays, chicken embryo chorioallantoic membrane (CAM) test, chicken embryo yolk sac membrane (YSM) test and transplantation tumor nude mice model were performed. The TCGA database, CGGA database and clinical tissue samples were used to analyze CXCL8’s significance on prognosis for patients with glioma.ResultsCXCL8 expression was significantly up-regulated in methionine-restricted tolerance cells, it also activated vascular system development and triggered angiogenesis. CXCL8 expression is negatively correlated with survival prognosis in gliomas.ConclusionsGlioma cells promote angiogenesis in methionine-restricted environments through the activation of CXCL8, compensating for nutrient deprivation, and possibly contributing to the failure of antiangiogenic therapy.

Cyclanoline Reverses Cisplatin Resistance in Bladder Cancer Cells by Inhibiting the JAK2/STAT3 Pathway.

Cisplatin is a key therapeutic agent for bladder cancer, yet the emergence of cisplatin resistance presents a significant clinical challenge. This study aims to investigate the potential and mechanisms of cyclanoline (Cyc) in overcoming cisplatin resistance. Cisplatin-resistant T24 and BIU-87 cell models (T24/DR and BIU-87/DR) were established by increasing gradual concentration. Western Blot (WB) assessed the phosphorylation of STAT3, JAK2, and JAK3. T24/DR and BIU-87/DR cell lines were treated with selective STAT3 phosphorylation modulators, and cell viability was evaluated by CCK-8. Cells were subjected to cisplatin, Cyc, or their combination. Immunofluorescence (IHC) examined p-STAT3 expression. Protein and mRNA levels of apoptosis-related and cell cycle-related factors were measured. Changes in proliferation, invasion, migration, apoptosis, and cell cycle were monitored. In vivo, subcutaneous tumor transplantation models in nude mice were established, assessing tumor volume and weight. Changes in bladder cancer tissues were observed through HE staining, and the p-STAT3 was assessed via WB and IHC. Cisplatin-resistant cell lines were successfully established, demonstrating increased phosphorylation of STAT3, JAK2, and JAK3. Cisplatin or Cyc treatment decreased p-STAT3, inhibited invasion and migration, and induced apoptosis and cell cycle arrest in the G0/G1 phase in vitro. In vivo, tumor growth was significantly suppressed, with extensive tumor cell death. IHC and WB consistently showed a substantial downregulation of STAT3 phosphorylation. These changes were more pronounced when cisplatin and Cyc were administered in combination. Cyc reverses cisplatin resistance via JAK/STAT3 inhibition in bladder cancer, offering a potential clinical strategy to enhance cisplatin efficacy in treating bladder cancer.

DEAD/H-box helicase 11 is transcriptionally activated by Yin Yang-1 and accelerates oral squamous cell carcinoma progression.

Oral squamous cell carcinoma (OSCC) is the most common oral malignancy. DEAD/H-box helicase 11 (DDX11), a DNA helicase, has been implicated in the progression of several cancers. Yet, the precise function of DDX11 in OSCC is poorly understood. The DDX11 expression in OSCC cells and normal oral keratinocytes was evaluated in the Gene Expression Omnibus database (GSE146483 and GSE31853). SCC-4 and CAL-27 cells expressing doxycycline-inducible DDX11 or DDX11 shRNA were generated by lentiviral infection. The role of DDX11 in OSCC cells was determined by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, colony formation assay, flow cytometry assay, TUNEL staining, and western blot. The effects of DDX11 on tumor growth were explored in a xenograft nude mouse model. The relationship between DDX11 and transcription factor Yin Yang-1 (YY1) was researched using the dual luciferase report assay and chromatin immunoprecipitation assay. DDX11 expression was significantly upregulated in OSCC cells. Knockdown of DDX11 inhibited cell proliferation, induced cell cycle arrest, and suppressed PI3K-AKT pathway, while DDX11 overexpression showed opposite effects. The number of apoptotic cells was increased in DDX11 silenced cells. DDX11 upregulation or knockdown accelerated or suppressed tumor growth in vivo, respectively. Moreover, the YY1 bound and activated the DDX11 promoter, resulting in increasing DDX11 expression. Forced expression DDX11 reversed the anticancer effects of YY1 silencing on OSCC cells. DDX11 has tumor-promoting function in OSCC and is transcriptionally regulated by YY1, indicating that DDX11 may serve as a potential target for the OSCC treatment.

Qingrexiaoji Recipe Regulates the Differentiation of M2 TAM via miR-29 in GC.

Gastric cancer, one of the most familiar adenocarcinomas of the gastrointestinal tract, ranks third in the world in cancer-related deaths. Traditional Chinese medicine can suppress the growth of tumors, and the underlying mechanism may be associated with the tumor microenvironment. Here, we investigated the anti-cancer effects of the Qingrexiaoji recipe on gastric cancer and the underlying molecular mechanism. An in vivo nude mouse model was established, and the expression of CD206, CD80, and M2 phenotype-related proteins (Arg-1, Fizz1) was obtained by flow cytometry and western blotting. The expressions of the M2 phenotype-related cytokines were examined by ELISA. Qingrexiaoji recipe inhibited gastric tumor growth and downregulated the expression of CD206, IFN-γ, IL-13, IL-4, and TNF-α in vivo. Qingrexiaoji recipe deceased M2 phenotypic polarization by upregulating microRNA (miR)-29a-3p level. Luciferase activity assays showed that HDAC4 is a potential target of miR-29a-3p. In cells co-transfected with HDAC4 siRNA and miR-29a-3p inhibitor and treated with IL-4 and Qingrexiaoji recipe, the miR-29a-3p inhibitorinduced increase of M2 phenotypic polarization was reversed. In summary, these results suggested that the Qingrexiaoji recipe regulated M2 macrophage polarization by regulating miR-29a-3p/HDAC4, providing a different and innovative treatment for gastric cancer.

Accurate and Safe Tumor Targeting of Orally-administered Salmonella typhimurium A1-R Leads to Regression of an Aggressive Fibrosarcoma in Nude Mice.

Salmonella typhimurium A1-R has been shown to target and inhibit many types of cancers in mouse models without continuous infection of normal tissue. The objective of the present study was to determine the effective dose of orally-administered Salmonella typhimurium A1-R, expressing-green fluorescent protein (GFP), on an HT1080 human-fibrosarcoma nude-mouse model. The HT1080-human- fibrosarcoma nude-mouse models were randomized into the following three groups: G1: untreated control; G2: Oral Salmonella typhimurium A1-R (5×107 colony forming units [CFU]/body, twice a week, 2 weeks); G3: Oral Salmonella typhimurium A1-R (3.3×108 CFU/body, twice a week, 2 weeks). Each group comprised five mice. Body weight and tumor volume were measured twice a week. The number of colonies of Salmonella typhimurium A1-R-GFP in excised tumors and excised livers in groups G2 and G3 were determined on day 3, day 7 and 14 by growth on agar plates. Tukey-Kramer analysis was used to examine the relationships between variables. Statistically-significant results are defined as those with p≤0.05. Salmonella typhimurium A1-R was administered orally at a dose of 3.3×108 CFU, which successfully regressed the HT1080 tumor in nude mice. However, this effect was not observed at a lower dose of 5×107 CFU. After administering Salmonella typhimurium A1-R at 3.3×108 CFU, tumors and liver tissues were harvested, homogenized, and cultured on days 3, 7 and 14. Resulting GFP-expressing Salmonella typhimurium A1-R colonies were then counted. The number of GFP-bacterial colonies derived from excised tumors at intervals of 3, 7, and 14 days increased over time post-administration of oral GFP-Salmonella typhimurium. Conversely, the number of GFP-Salmonella typhimurium A1-R colonies that could be grown from excised livers decreased over time, following oral administration of GFP-Salmonella typhimurium. Additionally, the GFP-bacterial colonies grown from the excised tumors were significantly larger than those grown from the excised livers. The present study showed that an aggressive fibrosarcoma could be regressed by orally-administered Salmonella typhimurium A1-R which accurately targeted tumors without continuous growth in normal organs. The present results suggested the potential of orally-administered Salmonella typhimurium A1-R as a probiotic to treat aggressive soft-tissue sarcoma.

Tetrahedral Framework Nucleic Acid-Loaded Retinoic Acid Promotes Osteosarcoma Stem Cell Clearance.

Metastatic osteosarcoma is a commonly seen malignant tumor in adolescents, with a five year survival rate of approximately 20% and a lack of treatment options. Osteosarcoma cancer stem cells are considered to be important drivers of the metastasis of osteosarcoma, and therefore their clearance is considered a promising strategy for treating metastatic osteosarcoma. In the relevant literature, retinoic acid (ATRA) is considered effective for eliminating osteosarcoma stem cells, but it has some inherent disadvantages, including poor solubility, difficulty in entering cells, and structural instability. Tetrahedral framework nucleic acids (tFNAs) are a type of nanoparticles that can carry small-molecule drugs into cells to exert therapeutic effects. Therefore, we designed and synthesized a nanoparticle named T-ATRA by using tFNAs to load ATRA and studied its effect in a nude mouse model. T-ATRA is more effective than ATRA in the clearance of osteosarcoma stem cells and in inhibiting osteosarcoma cell metastasis via the Wnt signaling pathway, thus prolonging the survival time of nude mice with osteosarcoma.

Delivery of BikDD proapoptotic gene in Peptide-18-targeted Poly(2-oxazoline)-DOPE nanoliposomes for breast cancer models.

Breast cancer is one of the most common cancers and a significant cause of death in females worldwide. For effective breast cancer treatment, using systems with a promising delivery of anticancer agents is an important strategy. Peptide 18 (P18), a tumor-homing peptide, shows a high binding affinity toward breast cancer cells. Nanoliposomes are known to have enhanced accumulation ability in tumors with longer systemic circulation. In this study, Poly (2-ethyl-2-oxazoline) (PEtOx) polymers conjugated with DOPE are used to prepare PEtOx-DOPE nanoliposomes. BikDD, a mutant form of the Bik gene and a member of the BH3-only proapoptotic genes, mimics the constitutively phosphorylated form of the gene. To the best of our knowledge, this study presents a novel approach by investigating P18-conjugated PEtOx-DOPE nanoliposomes (P18-PEtOx-DOPE) for the targeted delivery of BikDD to the AU565 breast cancer model. A site-directed mutated BikDD was loaded into P18-PEtOx-DOPE nanoliposomes, and the targeted drug delivery system was assessed in in vitro and in vivo breast cancer models for efficiency, safety, and efficacy. The increased Bik mRNA expression levels in AU565 cells suggest a high effectiveness of the targeting PEtOx-DOPE nanoliposomes. Following the in vitro studies, the delivery of BikDD by P18-PEtOx-DOPE nanoliposomes was analyzed in CD-1 nude mice models. The animal study showed no significant difference in the tumor volume of the CD-1 nude mice treated with P18-PEtOx-DOPE-BikDD nanoliposomes compared to the free delivery of BikDD. Our preclinical studies suggest that P18-PEtOx-DOPE-BikDD nanoliposomes may be promising gene carriers for targeted breast cancer therapy. Thus, further studies should be carried out to determine the prolonged use of this drug delivery system in breast cancer therapy.

Unraveling the mechanisms of RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway

BackgroundRECQL4 is a member of the DNA helicase family and is critical for DNA replication, DNA damage repair, and tumor progression. However, its specific role in cervical cancer remains uncertain. MethodsIn this study, we aimed to investigate the impact of RECQL4 on cervical cancer prognosis using clinical specimens from The Cancer Genome Atlas. We evaluated the malignant effects of RECQL4 through various experimental assays including cell Cell Counting Kit-8, EdU, colony formation, cell cycle analysis, cell apoptosis, scratch, and Transwell assays. We explored the mechanisms of RECQL4-regulated malignancy using analyses of bioinformatics, RNA sequencing data, polymerase chain reaction (PCR), western blotting, and cell immunofluorescence experiments. Furthermore, we validated the effects of RECQL4 knockdown on tumor growth using subcutaneous tumor models in nude mice. ResultsRECQL4 was upregulated in cervical cancer and correlated with prognosis, demonstrating a positive relationship with tumor mutational burden. Knockdown of RECQL4 inhibits cervical cancer cell proliferation, migration, and invasion, suppresses epithelial-mesenchymal transition status, induces cell cycle arrest, and promotes apoptosis. Mechanistically, RECQL4 mediated malignancy through the PI3K/AKT pathway and reduced nuclear β-catenin expression. In vivo studies further confirmed that RECQL4 knockout significantly inhibited tumor growth. ConclusionsOur findings provide novel insights into the mechanism behind RECQL4-mediated cervical cancer progression through the PI3K/AKT pathway. Furthermore, our study suggests potential therapeutic strategies for targeting RECQL4 in cervical cancer treatment.

ANGPTL4 plays a paradoxical role in gastric cancer through the LGALS7 and Hedgehog pathways.

Gastric cancer (GC) is a malignant disease worldwide. Angiopoietin-like protein 4 (ANGPTL4) plays a role in pathophysiological processes, including metabolic reprogramming, angiogenesis, proliferation, and metastasis. Current evidence shows conflicting findings regarding the role of ANGPTL4 in the progression of GC. ANGPTL4 in GC was confirmed through bioinformatic analysis and immunofluorescence staining. The impact of ANGPTL4 was subsequently validated in GC cell lines using various assays, including 5-ethynyl-2-deoxyuridine (EdU), 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), Flow Cytometry (FCM), wound healing, transwell, tube formation, chorioallantoic membrane model, and nude mouse model assays. RNA-seq analysis, polymerase chain reaction (PCR), western blotting (WB), immunofluorescence (IF) and coimmunoprecipitation (co-IP) were conducted to determine the potential downstream mechanism of ANGPTL4. In SNU5 and MKN7 cells, ANGPTL4 was found to augment proliferation, migration, invasion, evasion of apoptosis, and angiogenesis. Conversely, in the AGS cell line, ANGPTL4 was observed to suppress these processes. Notably, the overexpression of ANGPTL4 in AGS cells led to the upregulation of LGALS7, which has emerged as a pivotal factor contributing to the manifestation of an anticancer phenotype induced by ANGPTL4. LGALS7, which is involved in the regulation of the hedgehog pathway and subsequent promotion of GC progression through various processes, such as proliferation, migration, apoptosis evasion, angiogenesis, and lymphangiogenesis, was found to contribute to the contradictory effects of ANGPTL4.

SLC45A4 is involved in malignant progression of ovarian cancer through glycolytic metabolic reprogramming

Tumor cells promote malignant behaviors such as proliferation, invasion, and metastasis of cancer cells through glucose metabolic reprogramming, but the role of the H-dependent sugar cotransporter SLC45A4 in regulating metabolic reprogramming in ovarian cancer (OC) remains largely unknown. This study aimed to investigate the effects of SLC45A4 silencing on the transcriptome spectrum of ovarian cancer cells (OCC), glucose uptake, lactic acid production, intracellular ATP levels, and the expression and activity of HIF-α glycolysis signaling pathway. The results showed that SLC45A4 is overexpressed in OC and its elevated expression correlates with adverse clinical outcomes in OC patients. Silencing of SLC45A4 significantly inhibited the proliferation, invasion, and metastasis of OCC by suppressing glucose uptake and glycolysis, and it also reduced the expression of HIF-α glycolysis signaling pathway in OC tissues. In vivo experiments using shRNA to knock down SLC45A4 in xenograft models in nude mice demonstrated a significant inhibition of tumor growth. These findings suggest that SLC45A4 silencing can restrain the malignant progression of OC by inhibiting glucose uptake in OCC and affecting the reprogramming of glycolytic energy metabolism, indicating that SLC45A4 may serve as a potential therapeutic target for OC intervention.

Interleukin-12 treatment reduces tumor growth and modulates the expression of CASKA and MIR-203 in athymic mice bearing tumors induced by the HGC-27 gastric cancer cell line

Gastric cancer (GC) is one of the most common malignant tumors in the digestive system and due to its poor prognosis, there is an increase in the demand for more effective anticancer therapies. Interleukins are potential anticancer agents which can modulate expression of cancer related genes and have therapeutic effects. Interleukin 12 (IL-12) exhibits potent anti-tumor, anti-angiogenic and anti-metastatic activities and represents the ideal candidate for tumor immunotherapy, due to its ability to activate both innate and adaptive immunities. The aim of this study was to evaluate the effect of IL-12 administration on GC tumor growth induced in the cancer xenograft nude mouse model. Tumor development was analyzed weekly and after 8 weeks, the animals were sacrificed for cytokine analysis (IL-4, TNF-alfa, IL-2, INF-gamma, IL-12, IL-10, TGF-beta) by ELISA. The tumor cells in the implanted areas of the animals that developed solid growth of the tumor (anatomopathological analysis was performed). We have also evaluated CASK and miR203 expression, two related cell invasion factors, in the induced tumors after administration of 6 n/kg IL-12. The development of tumor masses was observed in all groups of animals inoculated with HGC-27 neoplastic cells. In animals treated with 6 n/kg IL-12, there was no tumor development confirmed by anatomopathological analysis. Changes in the levels of pro and anti-inflammatory cytokines were also observed. Our results indicated that miR203 expression was elevated while CASK was downregulated. These results suggest that IL-12 treatment repress the tumor growth by induction of miR203 expression which in turn repress CASK expression.

A chemically defined, mechanically tunable, and bioactive hyaluronic acid/alginate double-network hydrogel for liver cancer organoid construction

Liver cancer organoids replicate the pathophysiology of primary tumors, making them ideal for drug screening and efficacy evaluation. However, their growth in complex, variable, animal-derived matrices hinders practical application. Here, we designed an easily accessible, chemically defined, biocompatible double-network hydrogel (HADR) using methacrylated hyaluronic acid (HAMA), sodium alginate (SA), methacrylated dopamine (DMA), and c(RGDFC) for liver cancer organoid culture. By optimizing critical extracellular matrix (ECM) parameters, the HADR hydrogel achieves compatibility with the physiological mechanics of the human liver and fosters the adhesion and proliferation of multiple cell types. In vitro drug efficacy tests showed that HepG2 cell line-derived liver cancer organoids exhibited higher IC50 values than 2D cultures, indicating greater drug resistance. Subcutaneous tumor models in nude mice revealed that HADR hydrogels created a microenvironment for HepG2 cells mirroring the natural tumor ECM, leading to increased tumor volume, denser cell arrangement, and concurrent microvascular development. In vivo drug efficacy evaluations indicated that DOX treatment downregulated Ki-67 and MMP-9 expression, inhibiting HepG2 cell proliferation, invasion, and metastasis. These findings demonstrate the potential of HADR hydrogels for liver cancer organoid culture, offering new strategies for personalized drug screening and efficacy evaluation.

MiR-149-3p targeting TMPRSS4 regulates the sensitivity to cisplatin to inhibit the progression of lung cancer.

Lung cancer cells tend to develop resistance to cisplatin (DDP) during continuous chemotherapy, making it crucial to improve DDP sensitivity to enhance therapeutic outcomes. The levels of miR-149-3p in lung tissues and cells, as well as the biological behaviors of lung cancer cells, were analyzed. H446/DDP and A549/DDP cell lines were established to investigate how miR-149-3p affects lung cancer cells' sensitivity to DDP. Bioinformatics analysis predicted transmembrane serine protease 4 (TMPRSS4) as a downstream target of miR-149-3p, which was subsequently confirmed. Western blot analysis was used to examine proteins related to migration, invasion, apoptosis, and TMPRSS4 expression. Additionally, a subcutaneous graft tumor model in nude mice was created to assess the impact of miR-149-3p on tumor growth. In lung cancer tissues and cells, miR-149-3p expression was reduced, while TMPRSS4 expression was elevated. Overexpression of miR-149-3p inhibited cancer progression, promoted apoptosis, and enhanced the chemosensitivity of lung cancer cells to DDP. Moreover, miR-149-3p negatively regulated TMPRSS4, reducing malignancy-associated characteristics of lung cancer cells and further improving their DDP sensitivity. In vivo, high miR-149-3p expression increased the chemosensitivity of cancer cells. In conclusion, miR-149-3p suppresses the aggressive progression of lung cancer by directly downregulating TMPRSS4 and enhances the responsiveness of lung cancer cells to DDP.

Bio-Inspired Nanodelivery Platform: Platelet Membrane-Cloaked Genistein Nanosystem for Targeted Lung Cancer Therapy.

Genistein (Gen), a natural polyphenolic compound, has emerged as a promising candidate for lung cancer treatment. However, the potential clinical application of Gen is limited due to its poor solubility, low bioavailability, and toxic side effects. To address these challenges, a biomimetic delivery platform with cell membranes derived from natural cells as carrier material was constructed. This innovative approach aims to facilitate targeted drug delivery and solve the problem of biocompatibility of synthetic materials. First, the liposomes (LPs) loaded with Gen (LPs@Gen) was prepared using the ethanol injection method. Subsequently, PLTM-LPs@Gen was obtained through co-extrusion after mixing platelet membrane (PLTM) and LPs@Gen. Additionally, the biological and physicochemical properties of PLTM-LPs@Gen were investigated. Finally, the targeting ability, therapeutic efficacy, and safety of PLTM-LPs@Gen for lung cancer were evaluated using both a cell model and a tumor-bearing nude mouse model. The optimal preparation ratio for LPs@Gen was Gen: soybean lecithin: cholesterol: DSPE-PEG2000 (3:30:5:10, mass ratio), while the ideal fusion ratio of LPs@Gen and PLTM was 1:1. The particle size of PLTM-LPs@Gen was 108.33 ± 1.06 nm, and the encapsulation efficiency and drug loading were 94.29% and 3.09% respectively. Gen was released continuously and slowly from PLTM-LPs@Gen. Moreover, PLTM-LPs@Gen exhibited good stability within one week. The results of in vitro cellular uptake and in vivo distribution experiments indicated that the carrier material, PLTM-LPs, has the immune escape ability and tumor targeting ability. Consequently, it showed better therapeutic effects than free drugs and traditional LPs in vitro and in vivo tumor models. In addition, safety experiments demonstrated that PLTM-LPs@Gen possesses good biocompatibility. Biomimetic nanomedicine provides a new strategy for the precision treatment of lung cancer in clinical practice.

N6-methyladenosine-mediated upregulation of LNCAROD confers radioresistance in esophageal squamous cell carcinoma through stabilizing PARP1.

Radiotherapy is a primary therapeutic modality for esophageal squamous cell carcinoma (ESCC), but its effectiveness is still restricted due to the resistance of cancer cells to radiation. Long non-coding RNAs (lncRNAs) and N6-methyladenosine (m6A) have been shown to play significant roles in tumour radioresistance. However, the precise manifestation and role of m6A-modified lncRNAs in ESCC radioresistance remain unclear. Bioinformatics analysis was conducted to identify m6A-modified lncRNAs implicated in the radioresistance of ESCC. A series of functional experiments were performed to investigate the function of LNCAROD in ESCC. Methylated RNA immunoprecipitation, chromatin isolation by RNA purification-mass spectrometry, RNA immunoprecipitation, and co-immunoprecipitation experiments were performed to explore the mechanism of m6A-mediated upregulation of LNCAROD expression and the downstream mechanism enhancing the radioresistance of ESCC. The efficacy of LNCAROD in vivo was assessed using murine xenograft models. Herein, we identified LNCAROD as a novel METTL3-mediated lncRNA that enhanced radioresistance in ESCC cells and was post-transcriptionally stabilised by YTHDC1. Moreover, we confirmed that LNCAROD prevented ubiquitin-proteasome degradation of PARP1 protein by facilitating PARP1-NPM1 interaction, thereby contributing to homologous recombination-mediated DNA double-strand breaks repair and enhancing the radiation resistance of ESCC cells. Silencing LNCAROD in a nude mouse model of ESCC in vivo resulted in slower tumour growth and increased radiosensitivity. Our findings enhance the understanding of m6A-modified lncRNA-driven machinery in ESCC radioresistance and underscore the significance of LNCAROD in this context, thereby contributing to the development of a potential therapeutic target for ESCC patients.

Cancer cell membrane-camouflaged curcumin nanoparticles trigger ferroptosis for accurate gastric cancer therapy

Curcumin (CUR) is a hydrophobic polyphenol with considerable antitumor efficiency, but its clinical application is limited because of its poor solubility and low stability in aqueous solution and lack of targeting in vivo. Herein, we fabricated a tumor-targeting drug delivery system by loading CUR and cloaking homologous cancer cell membrane (CM) onto mesoporous silica NPs (MSN-CUR@CM). Characterization analysis showed that MSN-CUR@CM with a size of approximately 70 nm showed high water solubility and biocompatibility. Besides, MSN-CUR@CM exhibited tumor-targeting and excellent anti-gastric cancer efficiency both in vitro and in vivo owing to the cellular self-recognition of CM. In the established xenograft tumor nude mouse model, it was still significantly drug accumulated at the tumor site 72 h post administration. In addition, the mean tumor volume and weight of the MSN-CUR@CM group were was 3.97 and 7.47 times smaller than those of the CUR group. Ferroptosis, a type of non-apoptotic regulated cell death accompanied by iron-dependent lipid peroxidation, was triggered by MSN-CUR@CM. Further analysis demonstrated that MSN-CUR@CUR upregulated heme oxygenase (HO)-1 levels whereas it downregulated the expression of glutathione peroxidase 4 (GPX4) in SGC7901 cells in vitro, indicating that the canonical and noncanonical ferroptosis pathways were regulated by MSN-CUR@CM. In conclusion, our study demonstrated that MSN-CUR@CM with high water solubility, biocompatibility, and tumor-targeting properties inhibited gastric cancer both in vitro and in vivo by triggering ferroptosis and provided an admirable cancer therapy efficacy.