Cancer Cell International最新文献

Background: Pancreatic cancer (PC) is characterized by high chemoresistance and poor prognosis. CUL2, a scaffold protein of E3 ubiquitin ligases, has been implicated in tumor progression, but its role in PC remains unclear.

Methods: CUL2 expression was analyzed in PC tissues and cell lines using TCGA and GEO datasets, qRT-PCR, Western blot, and immunohistochemistry analysis. The biological functions of CUL2 were investigated through gain- and loss-of-function studies in vitro. The impact of CUL2 overexpression on gemcitabine sensitivity was evaluated in xenograft models. Molecular mechanisms were explored using proteasome inhibitor MG132, co-immunoprecipitation, subcellular fractionation, and ferroptosis assessment.

Results: CUL2 was significantly upregulated in PC tissues and correlated with poor prognosis. CUL2 promoted PC cell proliferation, migration, and EMT. Mechanistically, CUL2 competed with NRF2 for KEAP1 binding, thereby preventing KEAP1-mediated NRF2 degradation and promoting NRF2 nuclear translocation. CUL2 promoted oxidative stress while activating NRF2-dependent antioxidant response. The CUL2-NRF2 axis suppressed ferroptosis and conferred gemcitabine resistance in PC cells. In xenograft models, CUL2 overexpression enhanced tumor growth and attenuated gemcitabine sensitivity through NRF2-mediated ferroptosis inhibition.

Conclusions: Our findings reveal a novel mechanism whereby CUL2 promotes PC progression and ferroptosis resistance through regulation of the KEAP1-NRF2 axis. CUL2 overexpression enhances cellular antioxidant capacity and maintains mitochondrial integrity, thereby conferring broad resistance to ferroptosis-inducing conditions. This study suggests that targeting the CUL2-NRF2 axis to enhance ferroptosis sensitivity might represent a promising therapeutic strategy for PC treatment.

Background: Current treatment strategies for high-grade gliomas have a limited overall patient benefit. Here, Methylated RNA immunoprecipitation sequencing (MeRIP-seq) of glioma was conducted to screen the lncRNA regulated by m6A modification in glioma, and provide an innovative chemotherapeutic strategy to improved the therapeutic efficacy.

Methods: To elucidate the impact and the molecular mechanism of ALKBH5/SH3RF3-AS1/SH3RF3 regulation on glioma malignancy, proliferation phenotypic assays, MeRIP-qPCR, RIP-qPCR and western blotting were used. Expressions and clinical significances of ALKBH5, SH3RF3-AS1, and SH3RF3 were assessed in tissue chip. Furthermore, we designed a nanodrug (Nano^PCPT/siRNA@U251) for the targeted co-delivery of CPT (targeting type Ⅰ topoisomerase) and si-SH3RF3-AS1 (inhibiting SH3RF3, a Rac1-JNK activator) in glioma treatment.

Results: SH3RF3-AS1 was demethylated and overexpressed in glioma. We elucidated the mechanistic link between ALKBH5-mediated N6-methyladenosine (m6A) modification and SH3RF3-AS1 expression, and the cis-regulation of SH3RF3-AS1 to SH3RF3. Clinically, the ALKBH5, SH3RF3-AS1, and SH3RF3 expression increased with increasing glioma grade, high SH3RF3-AS1 expression correlated with unfavorable 5-year overall survival and progression-free survival in a cohort of 148 glioma patients. SH3RF3-AS1 drived glioma progression and promoted chemoresistance to camptothecin (CPT). We designed a nanodrug (Nano^PCPT/siRNA@U251) for the targeted co-delivery of CPT (targeting type Ⅰ topoisomerase) and si-SH3RF3-AS1 (inhibiting SH3RF3, a Rac1-JNK activator) in glioma treatment, and it effectively suppressed glioma cell growth both in vivo and in vitro models.

Conclusion: Our findings provide valuable insights into the roles of m6A demethylation-mediated upregulation of SH3RF3-AS1 in supporting glioma proliferation and demonstrate the potential of Nano^PCPT/siRNA@U251 as an innovative chemotherapeutic strategy for glioma.

Background: Gallbladder cancer (GBC) is an aggressive malignant tumor that seriously threatens the survival of GBC patients. Laminin-γ2 (LAMC2), an important component of laminins, has been reported to facilitate cancer development and chemoresistance in several cancers. However, the biological effect of LAMC2 on GBC is still unclear.

Methods: LAMC2 expression was assessed in GBC specimens through proteomics and RNA-seq data. To evaluate the biological effects of LAMC2, we performed colony formation, sphere formation, wound healing, and transwell and invasion assays, along with an in vivo metastasis model. Additionally, we also explored the role of LAMC2 in GBC organoid. Finally, Western blot and RT-qPCR were employed to identify the molecular mechanism underlying LAMC2-mediated regulation of aggressive behavior in GBC.

Results: Here, we revealed that LAMC2 was overexpressed in GBC tissues and was positively correlated with poor patient outcomes. Furthermore, the genetic silencing of LAMC2 significantly inhibited GBC cell colony formation, sphere formation, and organoid growth. Additionally, LAMC2 deficiency impaired GBC cell metastasis in vitro and in vivo, accompanied by a reversal of the epithelial-mesenchymal transition (EMT) phenotype. Mechanistically, LAMC2 expression was induced by the canonical TGF-β/SMAD2 signaling pathway, and in turn, LAMC2 feedback enhanced the activity of TGF-β signaling by binding to TGF-β receptor II (TGF-βRII).

Conclusion: Our findings suggest that LAMC2 promotes GBC progression and metastasis, potentially by regulating the TGF-β signaling pathway. Therefore, LAMC2 could serve as a potential prognostic biomarker and therapeutic target for GBC.

Tumor growth, metastasis, and treatment response in renal cell carcinoma (RCC) are believed to be regulated by the tumor microenvironment (TME). However, the mechanisms underlying the genomic, transcriptomic, and epigenetic alterations in clear cell RCC progression remain incompletely understood. This study analyzed single-cell RNA sequencing data from public databases, including tissue samples from three patients with RCC and three matched pairs of immune cells from tumor tissue and peripheral blood to screen macrophages with differential expression in the TME. We found that a CD9⁺ macrophage population was identified in the RCC tumor tissue, suggesting a role for CD9-expressing macrophages in RCC progression. The function of these macrophages was further investigated through in vitro and in vivo experiments involving CD9 knockdown or overexpression. CD9 expression was elevated in RCC tissues compared to adjacent non-cancerous tissues. CD9 knockdown considerably inhibited the TME-induced macrophages (M2), while CD9-overexpressing macrophages markedly promoted RCC cell growth in vitro and in vivo. Moreover, this phenomenon may be associated with the orphan nuclear receptor NOR1//Nr4a3 activation by CD9. These findings indicated that macrophages in the TME exhibited distinct expression patterns during RCC progression and that CD9⁺ macrophages promoted RCC development, suggesting that CD9 may be a potential therapeutic target for inhibiting RCC progression.

Objective: Testicular germ cell tumors (TGCTs), the most prevalent malignancy in males aged 15-40 years, exhibit suboptimal prognosis despite therapeutic advances. This study aimed to identify novel diagnostic biomarkers and elucidate their molecular mechanisms in TGCTs pathogenesis.

Methods: Through integrated bioinformatics analysis of public TCGA(The Cancer Genome Atlas)datasets and clinical specimen validation (n = 14), we screened LINC01272 as a candidate biomarker. RNA immunoprecipitation (RIP) assays were employed to verify the interaction between LINC01272 and fused in sarcoma (FUS). Functional experiments including siRNA-mediated gene silencing, transwell migration/invasion assays, and CCK-8 proliferation tests were performed in TGCTs cell lines (Tcam-2 and NCCIT).

Results: LINC01272 is significantly highly expressed in TGCT tissues. High LINC01272 levels indicate shorter overall and recurrence-free survival periods for patients; the predictive value is particularly significant in the subgroup with low tumor mutation burden. Silencing LINC01272 can inhibit the migration, invasion and proliferation of Tcam-2 and NCCIT cells, and down-regulate N-cadherin and Vimentin, while up-regulating LAMA1. RIP assays confirmed the direct binding of LINC01272 to FUS. FUS silencing can replicate the tumor suppressive effect of LINC01272 deletion, while FUS overexpression can reverse the inhibition of migration, invasion and proliferation caused by LINC01272 silencing.

Conclusion: We identified the LINC01272-FUS axis as a critical regulatory pathway in TGCTs progression, providing mechanistic insights for developing liquid biopsy biomarkers and RNA-targeted therapies.

Glioma is a highly malignant brain tumor, and its characteristic immunosuppressive microenvironment is closely associated with poor patient prognosis. In this study, we aimed to investigate the regulatory role of the transcription factor NFE2L2 (nuclear factor erythroid 2-related factor 2) in glioma and its underlying molecular mechanisms. Analysis based on the TCGA database and clinical samples revealed that NFE2L2 is significantly overexpressed in glioma tissues, and its expression level is closely correlated with tumor immune infiltration, particularly showing a positive association with M2-like tumor-associated macrophage (TAM) infiltration. By establishing an in vitro TAM induction model, we observed that NFE2L2 expression was upregulated during M2-like macrophage polarization. Further gene overexpression experiments demonstrated that NFE2L2 significantly enhances the migratory and invasive capabilities of glioma cells. To explore its in vivo function, we constructed an NFE2L2-deficient mouse model. The results showed that NFE2L2 deficiency led to the remodeling of the tumor immune microenvironment, thereby significantly improving the therapeutic response to PD-1 immune checkpoint inhibitors and suppressing glioma progression. Combined transcriptomic and metabolomic analyses identified differential genes and metabolites associated with NFE2L2, revealing its critical role in promoting M2-like macrophage polarization and modulating the tumor microenvironment. In summary, NFE2L2 not only plays a pivotal role in glioma development but may also serve as a potential therapeutic target. Future studies will further explore the specific mechanisms by which NFE2L2 regulates macrophage polarization and its clinical application prospects in immunotherapy.

Metastatic bladder cancer (mBC) continues to resist current treatment approaches, largely because aberrant microRNAs (miRNAs) simultaneously fuel epithelial-mesenchymal transition, enable immune system evasion, and promote resistance to therapies. Mounting evidence pinpoints miR-21 as a key oncomiR that amplifies PI3K/AKT signaling, while miR-200c plays a counterbalancing role by maintaining epithelial traits and promoting apoptosis. This makes the combined strategy of suppressing miR-21 while restoring miR-200c an especially compelling, though technically intricate, therapeutic target. Recently, two-dimensional transition-metal carbides and nitrides-known as MXenes-have emerged as promising tools, thanks to their exceptionally high surface area, excellent conductivity, and customizable surface chemistry, all of which make them ideal for shielding miRNAs, delivering them selectively to tumors, and enabling real-time photothermal monitoring. In this review, we weave together insights from epidemiology, molecular oncology, and nanotechnology to chart a translational pathway for applying MXene-based theranostic systems in mBC. We compile mechanistic data regarding miR-21 and miR-200c, detail the MXene physicochemical traits crucial for RNA loading and biosensing, and critically assess polymer-, ligand-, and ion-intercalation methods that improve biocompatibility without compromising electrical performance. Notably, preclinical studies show that MXene scaffolds can co-deliver anti-miR-21 and miR-200c mimics, destroy tumors via near-infrared photothermal therapy, and allow for electrochemical tracking of miRNA activity inside tumors-together achieving a potent, combined blockade of metastatic processes. Persistent challenges, including oxidative degradation, dose-dependent toxicity, and large-scale manufacturing, are addressed alongside promising innovations such as biodegradable surface coatings and machine-learning-assisted material design. Altogether, dual-miRNA theranostics using MXenes hold immense promise as transformative tools for precision treatment of metastatic bladder cancer.

Background: Uveal melanoma (UM) is a highly aggressive malignancy with a metastatic risk that depends on the molecular subclass. This subclass can be determined through molecular characterization of tumor-derived tissue. With eye-sparing treatments, tumor tissue is rarely available for molecular testing. We hypothesized that minimal invasive biomarkers such as methylated cell-free DNA (cfDNA) or circulating tumor DNA (ctDNA) can be used for prognosis and monitoring of patients.

Methods: Plasma cfDNA was isolated from healthy blood donors (HBDs, N = 19) and UM patients (N = 22). Plasma was collected at baseline (localized disease, N = 13) and during follow-up (metastatic disease, N = 9) from independent patients with high metastatic risk (HR, N = 11) (monosomy 3 and/or BAP1-mutated tumor) or intermediate metastatic risk (IR, N = 11) (disomy 3 and/or SF3B1-mutated tumor). Methylation signatures were determined using genome-wide LpnPI-based methylated DNA sequencing (MeD-seq). Samples with a CpG/reads ratio < 20% (N = 3) were excluded. IchorCNA was used to estimate the tumor fraction. cfDNA samples with detectable tumor fraction (N = 2) were analyzed separately from the other cfDNA samples without detectable tumor fraction (N = 18) to reduce noise in downstream analyses. Differentially methylated regions (DMRs) were identified between the following predefined subgroups: UM (N = 11) vs. HBDs (N = 19), and HR (N = 10) vs. IR (N = 7). To visualize clustering, principal component analysis (PCA) and hierarchical clustering was performed on the DMRs with fold change > 2.0. Gene set enrichment analysis (GSEA, Z-score > 2.0 and p < 0.05) was performed to evaluate biological relevance.

Results: Distinct clustering was observed between UM and HBDs samples, and between HR and IR samples, although outliers were present in the latter comparison. GSEA implicated eight canonical pathways including the S100 Family Signaling Pathway and RAF/MAP kinase cascade, which are linked to tumorigenesis and immune processes.

Conclusion: This pilot study reports on cfDNA methylation signatures that differentiates UM patients from HBDs, and may distinguish between intermediate and high risk UM subgroups, supporting its prognostic potential. However, its role in monitoring disease progression requires further validation. Independent replication studies are warranted to confirm our findings and evaluate the clinical applicability in UM.