Cellular Oncology最新文献

Cancer stem cells (CSCs) are a highly plastic subpopulation of tumor cells with capabilities for self-renewal, therapy resistance, and metastasis. Recent evidence highlights lipid metabolic reprogramming as a central mechanism supporting these malignant traits. This review synthesizes current findings on key lipid metabolic processes in CSCs-including lipid uptake via CD36, intracellular storage in lipid droplets, de novo fatty acid synthesis by fatty acid synthase (FASN), fatty acid oxidation (FAO) regulated by carnitine palmitoyltransferase 1A (CPT1A), and cholesterol biosynthesis through the mevalonate pathway. Although many of these pathways are active in bulk cancer cells, CSCs demonstrate greater functional reliance on them, leading to enhanced survival, redox balance, and adaptation to therapy. These metabolic preferences vary by cancer type, underscoring the need for context-specific approaches. Moreover, stromal components of the tumor microenvironment (TME), such as cancer-associated fibroblasts, adipocytes, and mesenchymal stem cells, modulate CSC lipid metabolism through paracrine signals and substrate transfer, reinforcing CSC maintenance and drug resistance. Therapeutic strategies targeting lipid metabolism-such as inhibition of SCD1, CPT1A, and HMG-CoA reductase-have shown promising preclinical results in selectively depleting CSC populations and sensitizing tumors to treatment. However, challenges remain in preserving normal stem cell function, which also depends on lipid pathways. This review underscores the emerging significance of lipid metabolism as both a hallmark and vulnerability of CSCs, offering opportunities for novel targeted cancer therapies.

Background: Fbxo2 is part of the SKP1-Cullin-F-box (SCF) E3 ubiquitin ligase complex. While increasing evidence indicates that Fbxo2 influences tumorigenesis and progression in various human malignancies, its biological importance and molecular mechanisms in renal cell carcinoma (RCC) are poorly understood.

Methods: Bioinformatic analysis of publicly available datasets was utilized to determine the association between Fbxo2 expression and survival in RCC patients. CCK8, colony-formation, and EdU assays were carried out to measure cell proliferation after Fbxo2 modulation in RCC cells. Coimmunoprecipitation, mass spectrometry, Western blotting, and ubiquitin assays were performed to explore the molecular mechanism of Fbxo2-involved tumorigenesis in RCC.

Results: Fbxo2 suppresses RCC cell growth. Moreover, higher Fbxo2 expression was positively associated with improved overall survival in RCC patients. In RCC, Fbxo2 inhibition increased cell motility and proliferation and inhibited cell apoptosis. WEE1 was identified as a novel substrate of Fbxo2 in RCC. Fbxo2 binds to the kinase domain of WEE1 through its FBA domain. Consistently, in xenograft mouse models, Fbxo2 knockdown increased tumor growth, whereas WEE1 depletion partially abolishes the tumorigenic effects caused by Fbxo2 silencing in vivo.

Conclusions: Our research revealed that Fbxo2 impedes the progression of RCC by interacting with WEE1, promoting its ubiquitination and degradation. Therefore, targeting the Fbxo2/WEE1 axis may represent a promising therapeutic strategy for treating RCC.

Purpose: Epithelial-mesenchymal transition (EMT) plays critical roles in tumor progress and treatment resistance of ovarian cancer (OC), resulting in the most deadly gynecological cancer in women. However, the cell-intrinsic mechanism underlying EMT in OC remains less illuminated.

Method: SKOV3, the OC cell line, was treated with TGF-β to induce EMT or with SB431542, an inhibitor of the TGF-β signaling pathway, to reduce migration. The function of HBO1 in EMT was confirmed by knock-down or overexpression of HBO1 in SKOV3 cells. The role of HBO1 in cell proliferation and apoptosis of SKOV3 cells was analyzed by flow cytometry. The whole-genome transcriptome was used to compare significantly different genes in control and HBO1-KD SKOV3 cells. T-cell cytotoxicity assays were measured by an IVIS spectrum. The chromatin binding of HBO1 was investigated using CUT&Tag-seq.

Results: Here, we show that HBO1, a MYST histone acetyltransferase (HAT), is a cell-intrinsic determinant for EMT in OC cells. HBO1 is greatly elevated during TGF-β-triggered EMT in SKOV3 OC cells as well as in later stages of clinical OC samples. HBO1 Knock-down (KD) in SKOV3 cells blocks TGF-β-triggered EMT, migration, invasion and tumor formation in vivo. Interestingly, HBO1 KD in SKOV3 cells suppresses their resistance to CAR-T cells. Mechanistically, HBO1 co-binds the gene sets responsible for EMT with SMAD4 and orchestrates a gene regulatory network critical for tumor progression in SKOV3 cells.

Conclusion: HBO1 plays an essential onco-factor to drive EMT and promote the immunotherapy resistance in ovarian cancer cells. Together, we reveal a critical role of HBO1 mediated epigenetic mechanism in OC progression, providing an insight into designing new therapy strategies.

Background: Patients who survive the excessive inflammatory phase of sepsis experience prolonged immunoparalysis/immunosuppression. During this phase, the patient's immune system is severely impaired, which increases the patient's susceptibility to septic complications. Sepsis survivors have a significantly greater incidence of cancer, but the mechanism underlying this phenomenon is unknown.

Methods: We constructed two sepsis-melanoma models to assess the relationship between sepsis and sepsis-related concomitant cancer. In our investigation, we employed a range of experimental technique to elucidate the intricate mechanisms through which the immunoparalysis phase of sepsis facilitates melanoma progression. Furthermore, we induced trained immunity with oroxylin A (OA) to evaluate its ability to reverse immunoparalysis and subsequent tumor progression in sepsis-melanoma models.

Results: We showed that sepsis upregulated the serum level of interleukin (IL)-6 and the number of myeloid-derived suppressor cells (MDSCs), regulated G-MDSCs/M-MDSCs and inhibited CD8⁺T-cell function, which promoted melanoma progression. OA-induced trained immunity can reverse immunoparalysis, maintain the antitumor capacity of the immune system, and inhibit the development of sepsis-complicated melanoma. Notably, OA can target macrophage migration inhibitory factor (MIF) and downregulate the serum level of IL-6, which may be a crucial molecular mechanism by which OA induces trained immunity to reverse the immunoparalysis phase of sepsis.

Conclusion: Sepsis can promote cancer progression by upregulating MIF and IL-6, increasing the G-MDSCs/M-MDSCs ratio and reducing the number and function of CD8⁺ T cells, leading to immunoparalysis, while trained immunity can alleviate this progression. The findings of this study provide new strategies for preventing or treating sepsis-complicated cancer.

Purpose: To investigate the role of neuregulin (NRG) signaling in promoting head and neck squamous cell carcinoma (HNSCC) migration through HER3-dependent pathways and to assess the therapeutic potential of targeting the NRG/HER3 axis in mitigating perineural invasion.

Methods: NRG-driven migration was studied using DRG co-culture, wound healing assays, and HER3 inhibition (shRNA, AV-203). The biological function and biochemical effects of the HER3/HER2/FAK axis in response to NRG were analyzed via phosphorylation assays, knockdown, western blotting, and cell staining for protein expression.

Results: NRG promoted directional migration of FaDu and TU138 HNSCC cells through HER3/HER2 and HER3/PI3K interactions. HER3 inhibition (shRNA or AV-203) abolished HER3 phosphorylation, disrupted HER3-HER2 interactions, and suppressed AKT and ERK signaling. Wound healing assays confirmed that NRG enhances migration via HER3 activation. NRG also induced HER3-dependent FAK phosphorylation, and FAK knockdown or inhibition with PF228 significantly reduced NRG-driven migration, highlighting the critical role of HER3-FAK signaling.

Conclusion: NRG promotes HNSCC cell migration by activating HER3, forming HER3-HER2 and HER3-FAK complexes, and driving downstream AKT, ERK, and FAK signaling. Targeting the NRG/HER3 axis holds potential as a therapeutic strategy to address perineural invasion and associated clinical challenges in HNC.

Purpose: Ovarian cancer (OC) is the most lethal gynecological malignancy, with widespread metastasis and ascites being the leading causes of patient mortality. However, the mechanisms driving OC metastasis have not been sufficiently studied. This study aimed to investigate the mechanisms and key molecules promoting OC metastasis.

Methods: Public databases (StemChecker, GeneCards, GEO, and TCGA) were screened to identify metastasis-associated genes. Immunohistochemical staining and western blotting were employed to evaluate THEMIS2 expression and epithelial-mesenchymal transition (EMT) marker profiles across experimental groups. RNA sequencing coupled with pathway enrichment analysis revealed THEMIS2-regulated signaling pathways, while immunoprecipitation-mass spectrometry was utilized to identify THEMIS2 interaction partners. GST pull-down assays for active Rap1 quantified Rap1-GTP levels under varying THEMIS2 expression conditions. Wound healing and transwell invasion assays respectively assessed migratory and invasive capacities of OC cells following THEMIS2 expression perturbations in vitro. Abdominal cavity implantation metastasis model was established to evaluate OC cell colonization and invasive potential in vivo.

Results: THEMIS2 expression is significantly elevated in OC tissues compared to normal ovarian tissues, and its high expression correlates with poor prognosis and malignant features. Experimental manipulation of THEMIS2 levels revealed that knockdown impended the migratory and invasive capacities of OC cells both in vitro and in vivo, while its overexpression exacerbated metastasis. THEMIS2 is involved in EMT and cytoskeleton rearrangement. RNA-seq analysis revealed that THEMIS2 positively correlates with Rap1 signaling pathway. Inhibition of Rap1 activity reversed the metastasis-promoting effects induced by THEMIS2 overexpression both in vitro and in vivo. Mechanistically, we uncovered that THEMIS2 functions as a molecular scaffold that recruits TBK1 (TANK Binding Kinase 1) to DOCK4 (Dedicator of Cytokinesis 4), facilitating site-specific phosphorylation at serine 1787 (S1787). This post-translational modification enables DOCK4 to engage with CRKII, subsequently triggering Rap1 signaling activation. These findings suggest that THEMIS2 promotes the metastatic potential of OC cells via DOCK4-mediated activation of Rap1 signaling.

Conclusion: THEMIS2 may serve as a predictive biomarker for OC prognosis, and targeting the Rap1 signaling pathway with specific inhibitors represents a promising therapeutic strategy for OC treatment.

Introduction: Osterix, encoded by SP7, is a transcription factor crucial in osteoblast differentiation and bone formation. While initially characterised in bone development, emerging evidence suggests its involvement in cancer, particularly breast cancer metastasis to bone.

Methods: Osterix protein expression was evaluated in 1340 early-stage invasive breast tumours by immunohistochemistry. Cytoplasmic and nuclear expression levels were assessed and associations with clinicopathological variables and patient survival determined. Additionally, SP7 mRNA expression was examined in the METABRIC cohort of patients. Gene set enrichment analysis (GSEA) was performed to explore the role of osterix in the hallmarks of cancer genesets.

Results: Results revealed significant associations between reduced nuclear osterix protein expression and adverse clinicopathological features, including larger tumour size, higher grade, and poor Nottingham Prognostic Index. Low nuclear osterix protein expression was also linked to shorter breast cancer-specific survival and distant metastasis free survival, particularly in patients with HER2 positive tumours. No associations were found between SP7 mRNA expression and clinicopathological variables or survival outcomes. GSEA identified enrichment of genes involved in KRAS signaling in tumours with high SP7 expression.

Conclusion: These data suggest that reduced nuclear expression of osterix is associated with poor clinical outcome of breast cancer patients and may be of clinical relevance.

Objective: Radioresistance is a common cause of poor radiation therapy effectiveness for non-small cell lung cancer. Finding molecular targets or methods to enhance radiosensitivity or overcome radioresistance is crucial. This study aimed to investigate the effects of MDMX on modulating radiosensitivity in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC).

Methods: The expression of MDMX and its correlation with radiotherapy response were analyzed in 101 LUAD and LUSC patient samples. LUAD and LUSC cell lines (A549, SK-MES-1) and their radioresistant counterparts (A549R, SK-MES-1R) were used to assess the effects of MDMX and P53 on radiosensitivity through autophagy by using molecular assays and animal models.

Results: The expression of MDMX was decreased, but the autophagy was enhanced in radioresistant LUAD and LUSC cells. Overexpression of MDMX inhibited P53 activity, leading to autophagy suppression and increasing radiosensitivity. In contrast, P53 upregulation counteracted the effects of MDMX, resulting in increasing autophagy and radioresistance. The higher MDMX expression was associated with improved radiotherapy response and prolonged overall survival in LUAD and LUSC cells. The 5-year survival rate was 93.62% in the low MDMX expression group and 98.11% in the high MDMX expression group (P < 0.01).

Conclusion: MDMX enhances LUAD and LUSC radiosensitivity by downregulating P53-mediated autophagy. High MDMX expression correlated with better clinical outcomes, suggesting that MDMX could be a potential biomarker for predicting radiotherapy response and prognosis in LUAD and LUSC patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, associated with viral hepatitis, alcohol consumption, and non-alcoholic fatty liver disease. Hepatocyte nuclear factor 4 alpha (HNF4α), a crucial transcription factor for liver function (glucose and lipid metabolism, bile acid homeostasis, and cellular differentiation), is often dysregulated in HCC progression. This review provides a comprehensive overview of the role of HNF4α in hepatic oncogenesis, providing novel inshight into its regulatory effects on epithelial-mesenchymal transition (EMT), metabolic alterations (including the Warburg effect), cell cycle control, and tumor microenvironment. We also discuss therapeutic strategies targeting HNF4α focusing on restoring metabolic balance and inducing apoptosis. This integrated analysis advances our understanding of HNF4α's contribution to HCC and may pave the way for the development of targeted therapies (Fig. 1).

The relationship between bacterial activity and tumorigenesis has gained attention in recent years, complementing the well-established association between viruses and cancer. A recent study employed immunodetection of lipopolysaccharide (LPS) to demonstrate the presence of intracellular bacteria within cancer cells across various cancer types, including breast cancer. The authors proposed that these bacteria might play a role in tumor development. We sought to replicate these findings using the same experimental methods on an independent cohort of breast cancer cases. Our analysis of 129 samples revealed no evidence of LPS expression within cancer cells. Instead, LPS immunoreactivity was observed in ducts or immune cells, specifically macrophages, as expected. These discrepancies in LPS immunodetection warrant caution in interpreting the original findings, and further research is needed to clarify the potential role of intracellular bacteria in cancer development.