Cellular Oncology最新文献

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.

Purpose: P-cadherin (CDH3) is a transmembrane protein that plays a crucial role in maintaining the structural integrity of epithelial tissue and homeostasis. Its role in carcinogenesis remains a subject of debate, as its behavior can vary depending on the molecular context and the specific tumor cell model under study. In this study, we explored the role of P-cadherin in head and neck squamous cell carcinoma (HNSCC) and the mechanisms underlying its function.

Methods: We analyzed P-cadherin expression in HNSCC patients using The Cancer Genome Atlas (TCGA), The Chungnam National University Hospital (CNUH) cohort and Gene Expression Omnibus (GEO) database. For in vitro functional analysis, we conducted proliferation, migration, invasion, and western blot assays after either suppressing or overexpressing P-cadherin. For in vivo functional analysis, we utilized mouse xenograft models.

Results: P-cadherin was significantly overexpressed in tumor samples compared to normal samples in the TCGA-HNSCC and CNUH-HNSCC cohorts. P-cadherin knockdown resulted in decreased proliferation, migration, and invasion compared to control cells, while P-cadherin overexpression increased cell proliferation and migration in HNSCC cells. We discovered that c-Met functions as an upstream regulator of P-cadherin. Surprisingly, we found that P-cadherin knockdown increased the phosphorylation of c-Met and STAT3. Combining P-cadherin siRNA with the c-Met inhibitor SU11274 or c-Met siRNA resulted in a more effective reduction in HNSCC cell growth, both in vitro and in vivo, compared to either treatment alone.

Conclusion: Our study uncovered a previously unknown aspect of P-cadherin-mediated c-Met regulation. The enhanced activation of c-Met/STAT3 following P-cadherin inhibition could be responsible for the survival of resistant tumor cells. Therefore, dual inhibition of P-cadherin and c-Met may be an effective approach for treating HNSCC.

Chimeric antigen receptor (CAR) therapy has successfully treated relapsed/refractory hematological cancers. This strategy can effectively target tumor cells. However, despite positive outcomes in clinical applications, challenges remain to overcome. These hurdles pertain to the production of the drugs, solid tumor resistance, and side effects related to the treatment. Some cases have been missed during the drug preparation due to manufacturing issues, prolonged production times, and high costs. These challenges mainly arise from the in vitro manufacturing process, so reevaluating this process could minimize the number of missed patients. The immune cells are traditionally collected and sent to the laboratory; after several steps, the cells are modified to express the CAR gene before being injected back into the patient's body. During the in vivo method, the CAR gene is introduced to the immune cells inside the body. This allows for treatment to begin sooner, avoiding potential failures in drug preparation and the associated high costs. In this review, we will elaborate on the production and treatment process using in vivo CAR, examine the benefits and challenges of this approach, and ultimately present the available solutions for incorporating this treatment into clinical practice.

Purpose: Although 60-70% of diffuse large B-cell lymphoma (DLBCL) patients can be cured with the current standard of chemotherapy and immunotherapy, the remaining patients experience treatment resistance and have poor clinical outcomes. More effective strategies are needed for the DLBCL treatment.

Methods: Databases of clinical patients were analyzed to investigate potential functions of leukocyte immunoglobulin-like receptor B1 (LILRB1) in DLBCL. Short hairpin RNAs were used for validation of in vitro and in vivo function of LILRB1 in DLBCL. RNA-seq was applied to explore potential mechanism, western blot and chromatin immunoprecipitation techniques were used to characterize the underlying signaling of CREB-SORBS3 pathway.

Results: We found that LILRB1 was highly expressed in DLBCL cells and was adversely correlated with the overall survival of DLBCL patients. Knockdown of LILRB1 effectively inhibited the proliferation of DLBCL cells both in vitro and in vivo. Mechanistically, LILRB1 upregulated CREB/CREB phosphorylation and transactivated SORBS3 expression to maintain DLBCL cell proliferation and tumorigenicity.

Conclusion: In this work, we revealed that LILRB1 was highly expressed in DLBCL cells and was negatively correlated with patient survival. Furthermore, we found that the LILRB1-CREB-SORBS3 pathway played a role in maintaining the proliferation of DLBCL cells. These data suggest that LILRB1 might be a potential target for the treatment of DLBCL.

Purpose: Immunotherapy has transformed the neoadjuvant treatment landscape for patients with resectable locally advanced non-small cell lung cancer (NSCLC). However, a population of patients cannot obtain major pathologic response (MPR) and thus benefit less from neoadjuvant immunotherapy, highlighting the need to uncover the underlying mechanisms driving resistance to immunotherapy.

Methods: Two published single-cell RNA sequencing (scRNA-seq) datasets were used to analyze the subsets of cancer-associated fibroblasts (CAFs) and T cells and functional alterations after neoadjuvant immunotherapy. The stromal signature predicting ICI response was identified and validated using our local cohort with stage III NSCLC receiving neoadjuvant immunotherapy and other 4 public ICI transcriptomic cohorts.

Results: Non-MPR tumors showed higher enrichment of CAFs and increased extracellular matrix deposition than MPR tumors, as suggested by bioinformatic analysis. Further, CAF-mediated immune suppression may involve reciprocal interactions with T cells in addition to a physical barrier mechanism. In contrast, MPR tumors demonstrated therapy-induced activation of memory CD8⁺ T cells into an effector phenotype. Additionally, neoadjuvant immunotherapy resulted in expansion of precursor exhausted T (Texp) cells, which were remodeled into an anti-tumor phenotype. Notably, we identified metabolic heterogeneity within distinct T cell clusters during immunotherapy. Methionine recycling emerged as a predictive factor for T-cell differentiation and a favorable pathological response. The stromal signature was associated with ICI response, and this association was validated in five independent ICI transcriptomic cohorts.

Conclusion: These discoveries underscore the distinct tumor microenvironments in MPR and non-MPR patients and may elucidate resistance mechanisms to immunotherapy in NSCLC.