Tumor Suppressive Effects Research Articles

Latexin (LXN) enhances tumor immune surveillance in mice by inhibiting Treg cells through the macrophage exosome pathway.

Latexin (LXN) is a secreted protein with a molecular weight of 29 KD, which is considered a tumor suppressor and plays an important role in the inflammatory immune response. LXN is highly expressed in macrophages and regulates macrophage polarity and tumor immune escape, demonstrating excellent clinical potential. However, its mechanism is still unclear. In this study, a macrophage-T cell co-culture system is established to clarify the secretion of macrophage LXN into the extracellular through exosomes. The results indicate that LXN in macrophage-derived exosomes is functional, that is, LXN-enriched exosome inhibits CD4+T cell differentiation into Treg cells in vitro and in vivo, and exhibits good tumor suppressive effects. Based on this discovery, a biomimetic nanoparticle loaded with LXN protein (MØ@LXN-NPS) is designed and synthesized. Furthermore, the MØ@LXN-NPS shows excellent performance in both in vivo and in vitro, especially in enhancing tumor immune surveillance by inhibiting Treg cells in tumor microenvironment, thus exhibiting excellent anti-tumor activity. This study provides a demonstration for the transition of biomolecules from functional research to engineering applications. The excellent performance of MØ@LXN-NPS in tumor immune regulation suggests that the engineered biomimetic nanomedicine has good clinical application prospects.

A phase II double window of opportunity trial evaluating the oral TGF-beta receptor I inhibitor vactosertib in patients undergoing standard of care preoperative therapy for locally advanced esophageal adenocarcinoma.

TPS516 Background: Esophageal adenocarcinoma (EAC) is the seventh most common cancer globally and ranks sixth in overall mortality. Despite improvements in pre-operative therapy, EAC has a high recurrence rate, especially among patients whose tumors do not achieve pathologic complete response (pCR), thus there is a critical need to enhance pCR rate and improve long-term outcomes. We recently discovered that a subset of EACs are driven by tumor-intrinsic oncogenic TGFβ signaling and have identified two potential biomarkers to predict response to anti-TGFβ therapy. One of these biomarkers is enriched in poorly differentiated EAC. We hypothesize that TGFβ signaling blockade will exert a tumor-inhibitory effect in patients with EAC and propose a double window-of-opportunity trial to test if TGFβ receptor I inhibitor vactosertib can improve pCR and induce tumor metabolic response in patients undergoing neoadjuvant therapy for localized EAC. Methods: This phase II double window of opportunity study assesses the efficacy and pharmacodynamics of the oral TGFβ Receptor I inhibitor vactosertib in patients with locally advanced esophageal adenocarcinoma (EAC). Patients will be treated with single-agent vactosertib in two windows of opportunity: the first will be prior to initiation of standard of care neoadjuvant therapy and the second after completion of neoadjuvant therapy prior to surgery. Patients will be eligible if they have poorly differentiated EAC and are appropriate for neoadjuvant therapy followed by resection as per standard of care. The primary objectives are improvement in pCR compared to historical controls and metabolic response (decrease in fluorodeoxyglucose uptake by PET CT) in the primary tumor after the first window. Secondary objectives will evaluate biomarkers of response identified in preclinical studies. Pre- and post-first window of opportunity treatment biopsies will be obtained for correlative and exploratory analyses. Clinical trial information: NCT06044311 .

Chiral polypeptide hydrogels regulating local immune microenvironment and anti-tumor immune response

The impact of chirality on immune response has attracted great interest in cancer vaccine research recently. However, the study of chiral synthetic polypeptide hydrogels as cancer vaccines as well as of the impact of biomaterials themselves for antitumor immunotherapy has rarely been reported. Here, we show the key role of residue chirality of polypeptide hydrogels in antitumor immunity and local immune microenvironment regulation. Compared to poly(γ-ethyl-L-glutamate)-based hydrogels (L-Gel), poly(γ-ethyl-D-glutamate)-based hydrogels (D-Gel) induces enhanced level of immune cell infiltration. However, D-Gel causes higher levels of suppressive markers on antigen-presenting cells and even induces stronger T cell exhaustion than L-Gel. Finally, D-Gel establishes a local chronic inflammatory and immunosuppressive microenvironment and shows insufficient anti-tumor effects. Conversely, the milder host immune responses induced by L-Gel leads to more effective tumor inhibition. This study provides insights on the role of residue chirality in the regulation of local immune microenvironment and affecting antitumor immune response.

HIFU induces reprogramming of the tumor immune microenvironment in a pancreatic cancer mouse model.

This study evaluates the effects of different high-intensity focused ultrasound irradiation (HIFU) methods on local tumor suppression and systemic antitumor effects, including the abscopal effect, in a mouse model of pancreatic cancer. To ascertain the efficacy of the treatment, pancreatic cancer cells were injected into the thighs of mice and HIFU was applied on one side using continuous waves or trigger pulse waves. Then, tumor volume, tissue changes, and immune marker levels were analyzed. Both the irradiation methods suppressed tumor growth, with the trigger pulse wave showing stronger effects and the difference being significant. Tumor suppression was also observed on the non-irradiated side, suggesting an abscopal effect. These effects vary depending on the irradiation method used. We conclude that HIFU induces both local tumor suppression and a systemic immune response, suggesting its potential for combination with immunotherapy for the treatment of pancreatic cancer.

Abstract B030: Novel strategy to improve response of high risk HPV+ HNSCC to radiation therapy

Abstract Background: Improving understanding of head and neck squamous cell carcinoma (HNSCC) has led to the discovery of novel molecular markers to stratify risk and guide treatment decisions. Recently, we have identified two subtypes of HPV+ OPSCC – one with good prognosis and one with poor prognosis. The subtypes are distinct in many ways – somatic genes mutated, HPV viral oncogenes expression, the physical state of the viral genome (integrated vs episomal), as well as global mutation and methylation profiles. Intriguingly, all differences converge on intrinsic tumor NF-κB activity with constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD) driving significantly elevated radiation sensitivity and improved patient survival. NF-κB-based groups define an important clinically actionable prognostic biomarker in HPV+ HNSCC: one important goal is to de-escalate therapy for patients with molecularly low-risk tumors to improve quality of life amongst survivors, while another goal is to improve the cure for of patients with a high risk of treatment failure. Material and methods: We utilized HPV+ head and neck cancer cells, HPV+ HNSCC xenografted mouse model, patient-derived xenografts (PDX), as well as our novel fully immunocompetent mouse model of high risk HPV+ HNSCC; we applied targeted fractionated radiation. To activate NF-κB, we used two clinically applicable drugs with different mechanisms of action: Toll-like receptor 5 (TLR5) agonist and mitochondria-derived activator of caspases (SMAC) mimetic. Custom NF-κB NanoString panel contains our recently developed NF-κB gene signature along with HPV genes and housekeeping genes that are used to normalize the gene expression data. Results: Both drugs activated NF-κB in HPV+ HNSCC and significantly improved response of HPV+ head and neck cancer cells and tumors to radiation. Interestingly, TLR5 agonist alone had a strong tumor suppressing effect in low NF-κB HPV+ HNSCC; this effect was significantly better than 32 Gy focused radiation given in fractions of 4 Gy. Custom NF-κB NanoString panel is robustly prognostic with NF-κB active tumors having improved outcomes after chemoradiation. Conclusions: Because of the average relatively favorable prognosis of HPV+ HNSCC, urgent need for improved therapy for patients with aggressive high risk tumors is greatly undervalued. Here, we present a clinical assay to risk stratify patients with HPV+ HNSCC and begin to explore pharmacological activation of NF-κB as a strategy to sensitize high risk HPV+ HNSCC to radiation therapy. TLR5 agonist is well known for the remarkable normal tissue protective effects against radiation and other damaging conditions; the dual effect of entolimod – sensitization of HPV+ HNSCC to radiation, while simultaneously protecting normal tissues from severe side effects - may be useful for patients with high-risk HPV+ head and neck cancer in combination with radiotherapy. Citation Format: Sri Vemulamanda, Natalia Issaeva1, Aditi Kothari, Travis Schrank, Wendell G. Yarbrough. Novel strategy to improve response of high risk HPV+ HNSCC to radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B030.

Electrical Stimulation Generates Induced Tumor-Suppressing Cells, Offering a Potential Option for Combatting Breast Cancer and Bone Metastasis

Treating advanced metastatic cancer, particularly with bone metastasis, remains a significant challenge. In previous studies, induced tumor-suppressing (iTS) cells were successfully generated through genetic, chemical, and mechanical interventions. This study investigates the potential of electrical stimulation to generate iTS cells. Using a custom electrical stimulator with platinum electrodes, mesenchymal stem cells (MSCs) and Jurkat T cells were stimulated under optimized conditions (50 mV/cm, 10–100 Hz, 1 h). Conditioned medium (CM) from electrically stimulated cells demonstrated tumor-suppressing capabilities, inhibiting tumor cell migration, 3D spheroid growth, and cancer tissue fragment viability. Additionally, the CM reduced osteoclast maturation while promoting osteoblast differentiation. Proteomic analysis revealed enrichment of tumor-suppressing proteins, including histone H4, in the CM. Functional studies identified Piezo1 as a key mediator, as its knockdown significantly impaired the tumor-suppressive effects. Mechanistically, the process was distinct from other methods, such as mechanical vibration, with SUN1 inhibition showing no effect on iTS cell generation by electrical stimulation. These findings demonstrate the efficacy of electrical stimulation in enhancing the antitumor capabilities of MSCs and T cells, offering a novel approach to cancer therapy. Further exploration of this strategy could provide valuable insights into developing new treatments for metastatic cancer.

LINC02418 suppresses endometrial cancer progression via regulating miR-494-3p/RASGRF1 axis.

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulatory molecules in cancer biology. Among these, long intergenic non-protein coding RNA 02418 (LINC02418), a recently identified lncRNA, has been linked to endometrial cancer (EC), although its function and operational mechanisms are largely unclear. The present investigation aims to elucidate the molecular mechanism through which LINC02418 influences EC pathogenesis. We employed Western blotting and quantitative real-time PCR to analyze Ras protein specific guanine nucleotide releasing factor 1 (RASGRF1) and LINC02418 expression profiles in EC tissues and cell lines. Functional analyses, including cell proliferation, migration, and invasion assays, were conducted to evaluate the impact of LINC02418 overexpression on EC cells. Xenograft mouse models were established for in vivo validation. The molecular interactions between LINC02418, miR-494-3p, and RASGRF1 were characterized using luciferase reporter and RNA pull-down assays. LINC02418 expression was significantly downregulated in EC tissues and cell lines compared to their normal counterparts. Forced expression of LINC02418 significantly suppressed EC cell proliferation, migration, and invasion in vitro. In xenograft models, LINC02418 overexpression resulted in reduced tumor burden and enhanced cell death. Mechanistically, LINC02418 enhanced RASGRF1 expression by sequestering miR-494-3p, a finding substantiated by RNA pull-down assays. The tumor-suppressive effects of LINC02418 were partially reversed by RASGRF1 silencing and miR-494-3p overexpression. Clinical analyses revealed that reduced RASGRF1 expression correlated with poor histological differentiation, advanced tumor stages, and decreased overall survival in EC patients. Our findings establish LINC02418 as a tumor suppressor that regulates EC progression through modulation of the miR-494-3p/RASGRF1 axis, highlighting its potential as a therapeutic target in EC treatment.

Discovery of paradoxical genes: reevaluating the prognostic impact of overexpressed genes in cancer

Oncogenes are typically overexpressed in tumor tissues and often linked to poor prognosis. However, recent advancements in bioinformatics have revealed that many highly expressed genes in tumors are associated with better patient outcomes. These genes, which act as tumor suppressors, are referred to as “paradoxical genes.” Analyzing The Cancer Genome Atlas (TCGA) confirmed the widespread presence of paradoxical genes, and KEGG analysis revealed their role in regulating tumor metabolism. Mechanistically, discrepancies between gene and protein expression-affected by pre- and post-transcriptional modifications-may drive this phenomenon. Mechanisms like upstream open reading frames and alternative splicing contribute to these inconsistencies. Many paradoxical genes modulate the tumor immune microenvironment, exerting tumor-suppressive effects. Further analysis shows that the stage- and tumor-specific expression of these genes, along with their environmental sensitivity, influence their dual roles in various signaling pathways. These findings highlight the importance of paradoxical genes in resisting tumor progression and maintaining cellular homeostasis, offering new avenues for targeted cancer therapy.

Injectable hydrogel-assisted local lipopolysaccharide delivery improves immune checkpoint blockade therapy.

Tumor-associated macrophages (TAMs) significantly influence the clinical outcomes of immune checkpoint blockade (ICB) therapy. Strategies aimed at reprogramming TAMs from the immunosuppressive M2 phenotype to the pro-inflammatory M1 phenotype hold promise for enhancing ICB efficacy. Lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) ligand, can reprogram TAMs toward an M1 phenotype. However, the systemic application of LPS is restricted due to its pronounced pro-inflammatory properties, which limit safe dosing in cancer treatment. To address this, thermosensitive hydrogels offer a viable solution by optimizing drug bioavailability and reducing systemic dissemination. In our study, carboxymethyl chitosan (CS) was incorporated into Pluronic F127 to extend the hydrogel's degradation period, facilitating the localized delivery and accumulation of LPS within tumor sites. Peritumoral injection of this hydrogel enhanced the tumor-inhibitory effects of anti-PD-1 antibodies, significantly improving the survival of 4T1 tumor-bearing mice. The GelF127CS-LPS hydrogel also increased the expression of the activation marker on tumor-infiltrating dendritic cells, promoted a higher M1/M2 TAM ratio, and enhanced CD8+ T cell infiltration into tumors-key indicators of T-cell-mediated anti-tumor immunity. Notably, no significant liver or hematological toxicity was observed with GelF127CS-LPS treatment, underscoring its favorable safety profile. These findings demonstrate the potential of GelF127CS-LPS as a TAMs-modulating agent and a promising combinatorial strategy to boost ICB therapy effectiveness. STATEMENT OF SIGNIFICANCE: LPS, a potent TLR4 ligand, can reprogram tumor-associated macrophages (TAMs) toward an M1 phenotype, thereby contributing to tumor inhibition. However, its anti-tumor application is constrained by the contradiction between high-dose toxicity and insufficient efficacy at low doses. To address this issue, we developed a thermosensitive hydrogel encapsulating LPS, GelF127CS-LPS, which allows localized LPS release within the tumor area. This hydrogel reprograms TAMs at a picogram level of LPS to achieve a favorable M1/M2 ratio and promotes the activation of T cell-mediated antitumor immunity without observable toxicity. Consequently, when combined with immune checkpoint blockade (ICB), the hydrogel can inhibit tumor growth and improve overall survival. This study provides an effective method for tumor-targeted therapeutic LPS delivery to enhance the efficacy of ICB.

Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis

ObjectivesLeflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC).MethodsTo evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice.ResultsLEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization.ConclusionLEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.

From Flies to Humans: Conserved Roles of CEBPZ, NOC2L, and NOC3L in rRNA Processing and Tumorigenesis.

NOC1, NOC2, and NOC3 are conserved nucleolar proteins essential for regulating ribosomal RNA (rRNA) maturation, a process critical for cellular homeostasis. NOC1, in Drosophila and yeast, enhances nucleolar activity to sustain rRNA processing, whereas its depletion leads to impaired polysome formation, reduced protein synthesis, and apoptosis. These genes have vertebrate homologs called CEBPZ, NOC2L, and NOC3l. In this study, we demonstrated that the RNA-regulatory functions of CEBPZ are conserved in vertebrates, and we showed that CEBPZ leads to the accumulation of 45S-pre rRNA, with consequent reduction in protein synthesis. Gene Ontology and bioinformatic analyses of CEBPZ, NOC2L, and NOC3L in tumors highlight a significant correlation between their reduction and the processes that regulate rRNA and 60S ribosomal maturation. Comparative analysis of their expression in tumor databases revealed that CEBPZ, NOC2L, and NOC3L exhibit contrasting expression patterns across tumor types. This dual role suggests that their overexpression promotes tumor growth, whereas reduced expression may exert tumor-suppressive effects, uncovering unexpected regulatory functions exerted by these proteins in cancer.

Gut colonization of Bacteroides plebeius suppresses colitis-associated colon cancer development.

Colon cancer development may be initiated by multiple factors, including chronic inflammation, genetic disposition, and gut dysbiosis. The loss of beneficial bacteria and increased abundance of detrimental microbes exacerbates disease progression. Bacteroides plebeius (B. plebeius) is a human gut microbe, and its colon colonization is enhanced by a seaweed-supplemented diet. We found that mice orally administered with B. plebeius and fed a diet containing 1% seaweed developed a unique gut microbial composition. By linear discriminant analysis effect size analysis, we found that B. plebeius colonization increased the abundance of Blautia coccoides and reduced the abundance of Akkermansia sp. and Dubosiella sp. We also showed that colonization of B. plebeius suppressed the colon tumor development induced by azoxymethane/dextran sulfate sodium in specific-pathogen-free mice, coinciding with a reduced abundance of Muribaculaceae sp., Closteridale sp., and Bilophila sp. Moreover, B. plebeius colonization in gnotobiotic mice resulted in enhanced production of selected metabolites, including propionic, taurocholic, cholic, alpha-, and beta-muricholic, as well as ursodeoxycholic acids. Importantly, some of these metabolites show anti-inflammatory and tumor-suppressive effects. We conclude that B. plebeius is able to restructure the gut microbial community and produce beneficial metabolites, leading to inhibition of colitis-associated colon cancer development.IMPORTANCEThis work delves into the pivotal role of gut microbiota in suppressing the progression of colitis-associated colon cancer. By investigating the impact of Bacteroides plebeius that can be colonized in mouse gut by feeding the animal with seaweed diet, we unveil a novel mechanism through which this beneficial bacterium reshapes the gut microbial community and produces metabolites with anti-inflammatory and tumor-suppressive properties. Such findings underscore the potential of harnessing specific microbes, like B. plebeius shown in this study, to modulate the gut ecosystem and mitigate the risk of colitis-associated colon cancer.

LHPP-P38 MAPK/ERK-ETS1 Axis Negative Feedback Signaling Restrains Progression in Breast Cancer.

Invasion and metastasis are major causes of mortality in breast cancer (BRCA) patients. LHPP, known for its tumor-suppressive effects, has an undefined role in BRCA. We found reduced LHPP protein in BRCA tissues, with lower levels correlating with poor patient outcomes. Invitro studies show LHPP inhibits BRCA cell proliferation, migration, invasion, and stemness. Invivo xenograft models support LHPP's role in curbing tumorigenesis and lung metastasis. Mechanistically, LHPP interacts with ERK and P38 MAPK, leading to their dephosphorylation and suppression of the MAPK pathway. We also reveal ETS1, a MAPK effector, repressing LHPP mRNA transcription, suggesting a LHPP-P38 MAPK/ERK-ETS1 negative feedback loop as a key regulatory mechanism in controlling BRCA invasion and metastasis.

Molecular Mechanisms of circKIF4A in Breast Cancer Progression.

Breast cancer (BC) is the most frequently diagnosed malignancy worldwide, necessitating continued research into its molecular mechanisms. Circular RNAs (circRNAs) are increasingly recognized for their role in various cancers, including BC. This study explores the role of circRNA kinesin family member 4A (circKIF4A) in BC progression and its underlying molecular mechanisms. BC cell lines were cultured, and circKIF4A expression was knocked down. Cell viability, proliferation, migration, and invasion were assessed using the Cell Counting Kit-8, colony formation assay, and Transwell assays. The expression of circKIF4A, miR-874-3p, and glycerophosphodiester phosphodiesterase domain-containing 5 (GDPD5) was quantified using qRT-PCR and Western blot analysis. Subcellular fractionation was performed to localize circKIF4A within the cell. The interactions between circKIF4A and miR-874-3p, as well as between miR-874-3p and GDPD5, were evaluated using RNA pull-down and dual-luciferase assays. Rescue experiments were conducted with miR-874-3p inhibition or GDPD5 overexpression to confirm the mechanistic pathway. circKIF4A was found to be upregulated in BC cells. Its knockdown significantly inhibited cell proliferation, migration, and invasion. circKIF4A acts as a sponge for miR-874-3p, reducing its expression. miR-874-3p targets and suppresses GDPD5, a key regulator in BC cell growth. Silencing miR-874-3p or overexpressing GDPD5 reversed the tumor-suppressive effects of circKIF4A knockdown. circKIF4A promotes BC cell proliferation and invasiveness by regulating the miR-874-3p/GDPD5 axis. These findings highlight a potential therapeutic target in BC and contribute to the understanding of circRNA involvement in cancer progression.

Mir-615-5p inhibits cervical cancer progression by targeting TMIGD2

BackgroundCervical cancer (CC) is a prevalent gynecological malignancy, contributing to a substantial number of fatalities among women. MicroRNAs (miRNAs) have emerged as promising biomarkers with significant potential for the early detection and prognosis of CC.ObjectiveThis study aimed to explore the clinical significance and biological role of miR-615-5p in CC, with the goal of identifying novel biomarkers for this disease.Materials and methodsThe levels of miR-615-5p and TMIGD2 mRNA in tissue samples and cells were quantified through quantitative reverse transcription real-time PCR, followed by statistical analyses to investigate the correlation between miR-615-5p and clinical data. The effects of miR-615-5p on the proliferation and metastasis of CC cells were evaluated using the Cell Counting Kit-8 and Transwell assays. The potential mechanism of miR-615-5p was elucidated by bioinformatics analyses and Dual-luciferase reporter assay. Western blotting was employed to measure the protein levels of TMIGD2.ResultsIn CC, the downregulation of miR-615-5p was related to poor prognosis and emerged as an independent prognostic factor. The levels of miR-615-5p were reduced in CC cells. miR-615-5p overexpression restrained the proliferation and metastasis of CC cells. Furthermore, TMIGD2 was identified as a target gene regulated by miR-615-5p, and its expression was notably elevated in CC. The influence of miR-615-5p on the biological behaviors of CC cells was mediated through the modulation of TMIGD2.ConclusionsDownregulation of miR-615-5p was a prognostic indicator of poor prognosis in CC. miR-615-5p exerted its tumor-suppressive effects by inhibiting cell growth and metastasis through the regulation of TMIGD2.

MiR-507 Acts as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting STEAP3.

In recent years, there has been a rise in the incidence of renal cell carcinoma (RCC), with metastatic RCC being a prevalent and significant contributor to mortality. While a regulatory role for microRNAs (miRNAs) in the development and progression of RCC has been recognized, their precise functions, molecular mechanisms, and potential clinical implications remain inadequately elucidated. Hence, this study aimed to explore the role of miR-507 in RCC and identify STEAP3 as a downstream target of miR-507. Bioinformatics analysis was used to analyze the expression of miR-507 and STEAP3 in RCC specimens. CCK-8, Transwell, and flow cytometry assays were used to assess the function of miR-507 in RCC cells. The connection between miR-507 and STEAP3 was confirmed through a luciferase reporter assay. The expression level of STEAP3, p53, and xCT was analyzed by western blotting. Bioinformatics analysis showed that miR-507 was expressed at low levels in RCC tissues and was linked to poor overall survival. STEAP3 was found to be significantly upregulated in RCC. Further, STEAP3 was shown to be targeted by miR-507. High levels of miR-507 reduced the expression of STEAP3, leading to stagnant cell viability, apoptosis, and migrative capacity. Whereas miR-507 knockdown reverted such a tendency. The study also discovered that miR-507 exerted its inhibitory effect through the op53/xCT pathway. Within RCC, miR-507 modulates the expression of SETAP3/p53/xCT axis, exhibiting a tumor suppressive effect. These discoveries offer present prospective biomarkers for both surveillance and treatment of RCC.

Synthesis and Application of a Novel Multifunctional Nanoprodrug for Synergistic Chemotherapy and Phototherapy with Hydrogen Sulfide Gas.

With the dilemma of limited efficacy of individual therapies, it is crucial to develop innovative combination therapy systems to target the complex pathogenesis of cancer. In this study, we designed a nanoprodrug ISL@MIL-101-ADT to facilitate synergistic delivery of hydrogen sulfide (H2S) and prodrug ISL for specific eradication of tumor cells with minimal toxicity and maximal efficacy. The nanoprodrug passively targeted tumors through enhanced permeation and retention effects, followed by disintegration and release of IR780, lonidamine (LND), and H2S. IR780 localizes LND to mitochondria to enhance therapeutic effects and turn on the phototherapy and chemotherapy when exposed to a laser; H2S inhibits procancer signaling pathways and mitochondrial function. In vivo experiments have demonstrated that ISL@MIL-101-ADT exhibits excellent pharmacokinetic properties and significant tumor inhibitory effects. Additionally, this nanoprodrug possesses outstanding photothermal and fluorescence imaging capabilities. Therefore, we strongly believe that the nanoprodrug present herein holds great potential for application in cancer therapy.

Hyodeoxycholic acid inhibits colorectal cancer proliferation through the FXR/EREG/EGFR axis.

The high morbidity and mortality rates of colorectal cancer (CRC) have been a public health concern globally, and the search for additional therapeutic options is imminent. Hyodeoxycholic acid (HDCA) has been receiving attention in recent years and has demonstrated potent efficacy in several diseases. Nonetheless, the antitumor effects and molecular pathways of HDCA in CRC remain largely unexplored. In this study, we investigated how HDCA influences the growth potential of CRC cells using techniques such as flow cytometry, Edu assay, CCK-8, colony formation assay, Western blot analysis, and animal experiments. It was found that HDCA treatment of CRC cells was able to significantly inhibit the proliferative capacity of the cells. Furthermore, it was discovered that HDCA primarily stimulated Farnesoid X Receptor (FXR) rather than Takeda G protein coupled receptor 5 (TGR5) to suppress CRC growth. It was also confirmed that HDCA inhibited the Epiregulin (EREG)/Epidermal Growth Factor Receptor (EGFR) pathway by activating FXR, and a negative correlation between FXR and EREG was analyzed in CRC tissue samples. Finally, in vivo animal studies confirmed that HDCA inhibited CRC proliferation without hepatotoxicity. Our findings indicate that HDCA suppresses the EREG/EGFR signaling route by activating FXR, thereby hindering the growth of CRC cells and demonstrating a tumor-inhibiting effect in CRC. This study may provide a new therapeutic strategy to improve the prognosis of CRC.

Ultrasound-activated erythrocyte membrane-camouflaged Pt (II) layered double hydroxide enhances PD-1 inhibitor efficacy in triple-negative breast cancer through cGAS-STING pathway-mediated immunogenic cell death.

Rationale: Immunogenic cell death (ICD) offers a promising avenue for the treatment of triple-negative breast cancer (TNBC). However, optimizing immune responses remains a formidable challenge. This study presents the design of RBCm@Pt-CoNi layered double hydroxide (RmPLH), an innovative sonosensitizer for sonodynamic therapy (SDT), aimed at enhancing the efficacy of programmed cell death protein 1 (PD-1) inhibitors by inducing robust ICD responses. Methods: Pt-CoNi layered double hydroxide (LDH) nanocages were synthesized using a two-step method, followed by functionalization with red blood cell membranes to prepare RmPLH. The in vitro assessments included evaluations of cell toxicity, cellular uptake, and sonodynamic effects of RmPLH. Key mechanisms-such as oxidative stress, DNA damage, pyroptosis, cGAS/STING pathway activation, and inhibition of cellular migration and invasion-were explored under varying treatment conditions in 4T1 cells. Tumor-bearing mice were employed to evaluate tumor-targeting capabilities and the synergistic tumor-suppressive effects of RmPLH combined with PD-1 inhibitors. Comprehensive safety evaluations, including blood tests, biochemical analyses, and histopathological examinations, were also conducted. Results: The synthesized Pt-CoNi LDH exhibited a uniform rhombic dodecahedral nanocage morphology with an average particle size of approximately 231 nm. Encapsulation with red blood cell membranes conferred prolonged systemic circulation, enhanced tumor targeting, and reduced immune clearance for RmPLH. Upon ultrasound (US) stimulation, the LDH released substantial levels of reactive oxygen species (ROS) and platinum ions. The ROS effectively induced endoplasmic reticulum stress and ferroptosis, while platinum ions facilitated DNA crosslinking, triggering significant DNA damage. ROS-induced pyroptosis released inflammatory mediators and damage-associated molecular patterns (DAMPs), which activated the cGAS/STING pathway and reinforced ICD. Combining RmPLH with PD-1 inhibitors significantly enhanced therapeutic efficacy against TNBC. Furthermore, safety assessments confirmed the excellent biocompatibility and biosafety of RmPLH. Conclusion: The integration of RmPLH with PD-1 inhibitors substantially amplifies ICD, fostering robust antigen-specific T cell immunity and offering a promising therapeutic strategy for TNBC. This study represents a pioneering application of Pt (II)-based LDH nanocages in oncology, laying a foundation for future innovations in tumor immunotherapy.

YY2-CYP51A1 signaling suppresses hepatocellular carcinoma progression by restraining de novo cholesterol biosynthesis.

Lipid accumulation is a frequently observed characteristic of cancer. Lipid accumulation is closely related to tumor progression, metastasis, and drug resistance; however, the mechanism underlying lipid metabolic reprogramming in tumor cells is not fully understood. Yin yang 2 (YY2) is a C2H2‑zinc finger transcription factor that exerts tumor-suppressive effects. However, its involvement in tumor cell lipid metabolic reprogramming remains unclear. In the present study, we identified YY2 as a novel regulator of cholesterol metabolism. We showed that YY2 suppressed cholesterol accumulation in hepatocellular carcinoma (HCC) cells by downregulating the transcriptional activity of cytochrome P450 family 51 subfamily A member 1 (CYP51A1), a key enzyme in de novo cholesterol biosynthesis. Subsequently, through in vitro and in vivo experiments, we demonstrated that this downregulation is crucial for the YY2 tumor suppressive effect. Together, our findings unraveled a previously unprecedented regulation of HCC cells cholesterol metabolism, and eventually, their tumorigenic potential, through YY2 negative regulation on CYP51A1 expression. This study revealed a novel regulatory mechanism of lipid metabolic reprogramming in tumor cells and provided insights into the molecular mechanism underlying the YY2 the suppressive effect. Furthermore, our findings suggest a potential antitumor therapeutic strategy targeting cholesterol metabolic reprogramming using YY2.