Journal of Experimental & Clinical Cancer Research最新文献

Background: Prostate cancer (PCa) is a globally prevalent malignancy in males and is imposing an increasing epidemiological burden. The androgen receptor (AR) signalling axis is fundamentally implicated in PCa tumorigenesis and disease progression. Although androgen deprivation therapy (ADT) elicits transient therapeutic responses in the majority of cases, progression to castration-resistant prostate cancer (CRPC) remains an almost universal clinical trajectory. Dysregulated lipid homeostasis, manifesting as intracellular lipid deposition, has been mechanistically linked to CRPC pathogenesis and therapeutic failure under enzalutamide regimens. However, effective strategies to mitigate lipid accumulation in PCa remain elusive.

Methods: STARD4, a key gene involved in lipid metabolism, was identified as functionally significant in PCa through integrated bioinformatics analysis of public databases. RT‒qPCR, western blot analysis, and IHC staining were performed to evaluate STARD4 expression, while Kaplan-Meier survival analysis, Gleason score, and tumor stage were performed to assess its clinical significance in PCa. The biological functions of STARD4 and its contribution to enzalutamide resistance were elucidated through in vitro and in vivo experiments. The effect of STARD4 on abnormal lipid accumulation in PCa cells was evaluated by Oil Red O (ORO) staining, while its impact on endoplasmic reticulum (ER) stress was assessed through ER-tracking imaging and transmission electron microscopy (TEM). Mechanistic exploration involves a combination of techniques, including RNA-seq analysis, Gene ontology analysis, coimmunoprecipitation (Co-IP), and GST pull-down assay, to analyse the interactions and potential mechanisms involving STARD4, AR, and E3 ubiquitin ligase UBE4B.

Results: In this study, we observed that STARD4 expression was markedly reduced in PCa tissues and was correlated with an adverse prognosis. STARD4 overexpression inhibited PCa cell proliferation, migration, and lipid accumulation while promoting apoptosis through ER stress. Mechanistically, STARD4 enhanced the interaction between UBE4B and AR, facilitating AR ubiquitination and degradation and thus suppressing AR signalling. Additionally, the upregulation of STARD4 expression enhanced sensitivity to enzalutamide in resistant cells by diminishing lipid accumulation and inhibiting the AR signalling pathway. In summary, STARD4 functions as a tumour suppressor in PCa by regulating cholesterol metabolism and modulating AR signalling.

Conclusions: Our findings identify STARD4 as a promising therapeutic target for reversing enzalutamide resistance in PCa while also providing novel insights for future research on lipid metabolism within the tumour microenvironment.

Background: The transcription factor Yin Yang 1 (YY1) and the Raf kinase inhibitory protein (RKIP) represent two molecular entities with diametrically opposed roles in cancer biology. They are key modulators of multiple cellular processes, including apoptosis, metastasis, and cell survival. YY1 functions predominantly as an oncogenic driver, promoting tumorigenesis, epithelial-mesenchymal transition (EMT), immune evasion, and resistance to chemo-immuno-therapy. In contrast, RKIP acts as a metastasis suppressor and chemo-immuno-sensitizer, inhibiting critical oncogenic signaling pathways. The inverse correlation between high YY1 and low RKIP expressions has been observed across various malignancies (such as prostate cancer, melanoma, colorectal cancer, cervical cancer, hematologic malignancies, etc.), suggesting a tightly regulated molecular axis influencing tumor progression and therapeutic response. This review systematically examines the contrasting roles of YY1 and RKIP in cancer pathogenesis (e.g. cell proliferation and cell cycle, angiogenesis, immune cells infiltration and immunosuppressive TME, check point inhibitors, resistance to apoptosis, cell energetics, etc.). Based on their opposing activities, we propose the term YYR-the YY1-RKIP regulatory network- to explain the interplay. YYR captures the bidirectional and context-dependent nature of their relationship for understanding transcriptional programming, immune suppression, tumor aggressiveness, and therapeutic resistance in cancer.

Conclusion: Understanding the dynamics of the YYR axis may offer new insights into prognostic markers and therapeutic strategies aimed at restoring tumor suppressor function and overcoming treatment resistance. Accordingly, we explore potential therapeutic strategies aimed at targeting YYR.

Background: Hepatocellular carcinoma (HCC) presents a significant therapeutic challenge, as current treatment options provide limited long-term benefits due to issues surrounding their effectiveness and associated adverse effects. Our previous research demonstrated that Proteoglycan-4 (PRG4) enhances the anti-proliferative effect of the multi-kinase inhibitor regorafenib in simple in vitro two-dimensional HCC models. In this study, we aimed to investigate the potential adjuvant role of PRG4 in improving the efficacy of regorafenib within both three-dimensional in vitro and in vivo HCC models.

Methods: Human HCC cells were engineered to stably overexpress PRG4. The effects of PRG4 on cell proliferation, both alone and in combination with regorafenib, were tested in monolayer cultures, Matrigel-embedded spheroids, and an orthotopic xenograft HCC mouse model. Additionally, transcriptomic profiling of spheroids generated from control or PRG4-overexpressing HCC cells, either untreated or treated with regorafenib, was performed.

Results: PRG4 expression partially inhibited HCC tumor growth in vivo and enhanced regorafenib antiproliferative activity, leading to a near-complete tumor regression. This synergistic PRG4 + regorafenib interaction in impairing HCC cell growth was further confirmed in 2D and 3D HCC models in vitro. In addition, PRG4 restrained angiogenesis by hindering endothelial tubulogenesis in vitro. By transcriptomic analysis of matrigel-embedded HCC cell spheroids exposed to PRG4 and/or regorafenib, PDGF pathway emerged as a target of PRG4 + regorafenib, corroborating the role of PRG4 in impairing angiogenesis. The G₀/G₁ phase of the cell cycle was more delayed in spheroids exposed to both PRG4 and regorafenib compared to those treated with regorafenib alone, relative to untreated cells.

Conclusions: PRG4 demonstrated antitumor activities in vivo and shows promise as an adjuvant to enhance therapeutic interventions in HCC.

Background: Tumor invasion and metastasis are strongly influenced by cell membrane fluidity, regulated by lipid metabolism. In choroidal melanoma (CM), a highly metastatic cancer, the relationship between lipid metabolism, membrane fluidity, and metastatic mechanisms remains unclear.

Methods: We examined m⁶A methylation in CM patient samples. Lipidomic profiling was performed in control, METTL14-silenced, or SCD1-silenced CM cells. Transcriptomics were analyzed after METTL14 manipulation. Transmission electron microscopy assessed ultrastructural changes, while multiplex immunohistochemistry validated the clinical relevance of the MAFG-METTL14-SCD1 axis. The anti-metastatic effect of combining the SCD1 inhibitor aramchol with a stearate-rich diet (S-HFD) was tested in nude mouse CM metastasis models.

Results: Lipidomics revealed that SCD1 promotes CM progression via cardiolipin and fatty acid metabolism pathways. Silencing SCD1 reduced membrane fluidity, while its upregulation in CM was driven by METTL14-mediated m⁶A methylation at the 2492 mRNA site. Elevated MAFG expression further activated METTL14. Mechanistically, this MAFG-METTL14-SCD1 axis enhanced CM invasiveness. In preclinical models, aramchol combined with S-HFD markedly suppressed distant metastasis.

Conclusions: Our study identifies SCD1-mediated lipid remodeling as a key driver of enhanced membrane fluidity and metastatic potential in CM. Inhibition of SCD1 increases lipid saturation, reduces membrane fluidity, induces oxidative stress, and suppresses liver and lung metastasis. The MAFG-METTL14-SCD1 axis thus represents a critical regulator of CM progression, and combined therapeutic targeting with aramchol and S-HFD offers promising translational potential.

The development and progression of gastrointestinal (GI) cancers not only depend on the malignancy of the tumor cells, but is also defined by the complex and adaptive nature of the tumor microenvironment (TME). The TME in GI cancers exhibits a complex internal structure, typically comprising cancer cells, cancer stem cells, cancer-associated fibroblasts, immune cells, and endothelial cells, all embedded within a dynamic extracellular matrix. This intricate ecosystem fuels tumor initiation, progression, metastasis, recurrence and therapy response through the heterogeneity and plasticity. Recent advances in single-cell sequencing have provided unprecedented resolution in profiling the cellular diversity and interactions within the TME. These technologies have uncovered previously unknown cell subtypes and intricate communication networks that drive therapy resistance and tumor relapse. In this review, we summarize and discuss the latest findings from single-cell sequencing of key cellular players and their interactions within the TME of GI cancers. We highlight single cell insights that are reshaping our understanding of tumor biology, with particular focus on their implications for overcoming therapy resistance and improving clinical outcomes. We believe that a deeper understanding of TME heterogeneity and plasticity at the single-cell level promises to transform the landscape of precision treatment in GI cancers.

Background: A key challenge in cancer immunotherapy is that tumor vaccines formulated with conventional aluminum adjuvants often fail to elicit potent cellular immunity and sustained antitumor responses. Glycyrrhizae polysaccharides (NGUP), characterized by significant immunomodulation, multi-target antitumor efficacy, and low toxicity, represent promising candidates for next-generation vaccine adjuvants.

Methods: We employed transcriptome analysis, quantitative real-time PCR, and Western blot assays to investigate the mechanism of NGUP in activating bone marrow-derived dendritic cells in vitro. Using confocal microscopy, small animal in vivo imaging, and flow cytometry, we examined the process of tumor antigen-specific T cell response activation by the liposomal vaccine (NGUPL@OVA) in vivo. The efficacy of NGUPL@OVA was evaluated in murine melanoma models (B16-OVA and B16-F10) through immunohistochemistry, immunofluorescence and H&E staining.

Results: NGUP activates dendritic cells through the TLR4/MyD88/TRAF6/NF-κB signaling pathway. NGUPL@OVA demonstrates efficient lymph node targeting capacity, significantly enhancing dendritic cell maturation and antigen cross-presentation, thereby promoting robust CD8⁺ T cell activation and inducing potent cellular immune responses with long-term immunological memory. In both prophylactic and therapeutic settings, NGUPL@OVA exhibits significant melanoma growth inhibition without observable toxic side effects.

Conclusions: NGUP as a novel vaccine adjuvant for cancer immunotherapy effectively overcomes key limitations of conventional aluminum adjuvants, including weak induction of cell-mediated immunity and significant adverse effects, while exhibiting superior immune-stimulating properties.