Cellular Oncology最新文献

Purpose: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.

Method: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

Results: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.

Conclusions: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

Purpose: Pediatric sarcomas are bone and soft tissue tumors that often exhibit high metastatic potential and refractory stem-like phenotypes, resulting in poor outcomes. Aggressive sarcomas frequently harbor a disrupted p53 pathway. However, whether pediatric sarcoma stemness is associated with abrogated p53 function and might be attenuated via p53 reactivation remains unclear.

Methods: We utilized a unique panel of pediatric sarcoma models and tumor tissue cohorts to investigate the correlation between the expression of stemness-related transcription factors, p53 pathway dysregulations, tumorigenicity in vivo, and clinicopathological features. TP53 mutation status was assessed by next-generation sequencing. Major findings were validated via shRNA-mediated silencing and functional assays. The p53 pathway-targeting drugs were used to explore the effects and selectivity of p53 reactivation against sarcoma cells with stem-like traits.

Results: We found that highly tumorigenic stem-like sarcoma cells exhibit dysregulated p53, making them vulnerable to drugs that restore wild-type p53 activity. Immunohistochemistry of mouse xenografts and human tumor tissues revealed that p53 dysregulations, together with enhanced expression of the stemness-related transcription factors SOX2 or KLF4, are crucial features in pediatric osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma development. p53 dysregulation appears to be an important step for sarcoma cells to acquire a fully stem-like phenotype, and p53-positive pediatric sarcomas exhibit a high frequency of early metastasis. Importantly, reactivating p53 signaling via MDM2/MDMX inhibition selectively induces apoptosis in aggressive, stem-like Ewing's sarcoma cells while sparing healthy fibroblasts.

Conclusions: Our results indicate that restoring canonical p53 activity provides a promising strategy for developing improved therapies for pediatric sarcomas with unfavorable stem-like traits.

Head and neck cancer (HNC) remains a major global health burden, prompting the need for innovative therapeutic strategies. This review examines the role of the cystine/glutamate antiporter (xCT) in HNC, specifically focusing on how xCT contributes to cancer progression through mechanisms such as redox imbalance, ferroptosis, and treatment resistance. The central questions addressed include how xCT dysregulation affects tumor biology and the potential for targeting xCT to enhance treatment outcomes. We explore recent developments in xCT-targeted current and emerging therapies, including xCT inhibitors and novel treatment modalities, and their role in addressing therapeutic challenges. This review aims to provide a comprehensive analysis of xCT as a therapeutic target and to outline future directions for research and clinical application.

Purpose: Terminal nucleotidyltransferase 5A (TENT5A), recently predicted as a non-canonical poly(A) polymerase, is critically involved in several human disorders including retinitis pigmentosa, cancer and obesity. However, the exact biological role of TENT5A in hepatocellular carcinoma (HCC) has not been elucidated.

Methods: The transcription level of TENT5A and clinical correlation were analyzed using the LIRI-JP cohort, the TCGA-LIHC cohort, and clinical tissue samples of HCC patients in our laboratory. Proliferation, migration, and invasion were detected with stably TENT5A overexpressing and knockdown HCC cells in vitro and in vivo. Chromatin immunoprecipitation and dual-luciferase reporter assay were performed to verify the binding of the target protein to DNA. Co-immunoprecipitation and GST pull-down assay combined with mass spectrometry (MS) were used to identify protein interactions.

Results: Our study presented here shows that TENT5A is downregulated in HCC tissues, suggesting a shorter overall survival for patients. Gain- and loss-of-function experiments reveal that TENT5A suppresses the proliferation and metastasis, and the residue Gly¹²² is of great importance to the role of TENT5A in HCC. More importantly, EGR1 (Early growth response 1) directly binds to the TENT5A promoter and promotes TENT5A expression. By interacting with RPL35, TENT5A is involved in ribosome biogenesis and exerts a negative regulatory effect on the mTOR pathway.

Conclusions: Our findings illustrate the role of the oncosuppressive function of TENT5A in HCC and suggest that the EGR1/TENT5A/RPL35 regulatory axis may be a promising target for therapeutic strategies in HCC.

Purpose: To explore the correlation between semi-quantitative parameters of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) scans findings and the clinical features of patients with acute leukemia (AL), as well as to evaluate the clinical utility of ¹⁸F-FDG PET/CT in the management of AL.

Methods: A retrospective study was conducted with 44 patients newly diagnosed with acute leukemia (AL) at Zhongnan Hospital of Wuhan University between January 2019 and August 2024.

Results: Multivariate analysis revealed that age at diagnosis of AL (odds ratio [OR]: 0.888, P < 0.01) and percentage of blasts in the peripheral blood (PB) (OR: 1.061, P < 0.05) were independent predictors of the appearance of active extramedullary disease (EMD). Kaplan-Meier survival analysis for patients with EMD(+) indicated that those with organ infiltration beyond the lymph nodes experienced markedly reduced overall survival (OS) compared to those without such infiltration (157 days and 806 days, respectively). Furthermore, in the AL subgroup with EMD, the ratio of the maximum standardized uptake value (SUVmax) in the bone marrow (BM) to SUVmax of the liver emerged as an independent prognostic factor for OS (Hazard ratio [HR]: 2.372; 95% confidence interval [CI]: 1.079-5.214, P < 0.05).

Conclusion: ¹⁸F-FDG PET/CT offers the benefits of being non-invasive and highly sensitive for the thorough evaluation of disease status in patients newly diagnosed with AL. Furthermore, the SUVmax BM/liver ratio is of significant clinical importance for prognosticating outcomes in patients with AL presenting EMD.

Purpose: Autophagy is frequently observed in tissues during the aging process, yet the tissues most strongly correlated with autophagy during aging and the underlying regulatory mechanisms remain inadequately understood. The purpose of this study is to identify the tissues with the highest correlation between autophagy and aging, and to explore the functions and mechanisms of autophagy in the aging tissue microenvironment.

Methods: Integrated bulk RNA-seq from over 7000 normal tissue samples, single-cell sequencing data from blood samples of different ages, more than 2000 acute myeloid leukemia (AML) bulk RNA-seq, and multiple sets of AML single-cell data. The datasets were analysed using various bioinformatic approaches.

Results: Blood tissue exhibited the highest positive correlation between autophagy and aging among healthy tissues. Single-cell resolution analysis revealed that in aged blood, classical monocytes (C. monocytes) are most closely associated with elevated autophagy levels. Increased autophagy in these monocytes correlated with a higher proportion of C. monocytes, with hypoxia identified as a crucial contributing factor. In AML, a representative myeloid blood disease, enhanced autophagy was accompanied by an increased proportionof C. monocytes. High autophagy levels in monocytes are associated with pro-inflammatory gene upregulation and Reactive Oxygen Species (ROS) accumulation, contributing to tissue aging.

Conclusion: This study revealed that autophagy is most strongly correlated with aging in blood tissue. Enhanced autophagy levels in C. monocytes demonstrate a positive correlation with increased secretion of pro-inflammatory factors and elevated production of ROS, which may contribute to a more rapid aging process. This discovery underscores the critical role of autophagy in blood aging and suggests potential therapeutic targets to mitigate aging-related health issues.

Purpose: Posttranslational modification significantly contributes to the transcriptional diversity of tumors. Adenosine deaminase acting on RNA 1 (ADAR1) and its mediated adenosine-to-inosine (A-to-I) editing have been reported to influence tumorigenesis across various cancer types. Nevertheless, the relationship between ADAR1 and radioresistence remains to be elucidated.

Methods: The protein expression was detected by immunohistochemistry and Western Blot, while the mRNA expression was measured by RT-qPCR. The tumor growth was evaluated by CCK8, colony formation assays, EdU assay, and in-vivo mouse model. γ-H2AX foci formation, neutral comet tailing assay, and clonogenic cell survival assay were performed to determine the DNA damage and radiosensitivity. RNA-seq was conducted to identify the main downstream effector. The interaction between ADAR1 and Rad18 was examined by immunofluorescence and co-immunoprecipitation.

Results: We reported that ADAR1 was upregulated and correlated with poor prognosis in non-small cell lung cancer (NSCLC). In addition, we demonstrated that silencing ADAR1 significantly impaired tumor growth and improved tumor sensitivity to radiotherapy in vitro and in vivo. Mechanistically, we found that Rad18, which has been established as a versatile modulator of DNA repair, was the major downstream effector of ADAR1. ADAR1 not only regulated Rad18 mRNA expression by E2F3 but also colocalized and interacted with Rad18. Finally, our rescue experiments demonstrated that ADAR1's protumorigenic functions were partially dependent on Rad18.

Conclusion: Our results revealed the role of ADAR1 in cooperation with Rad18 in modulating oncogenesis and radioresistance in NSCLC for the first time, and suggested the therapeutic potential of targeting ADAR1 in overcoming radioresistance.

Glioblastoma is the commonest and deadliest primary brain tumor. Glioblastoma is characterized by significant intra- and inter-tumoral heterogeneity, resistance to treatment and dismal prognoses despite decades of research in understanding its biological underpinnings. Encompassed within this heterogeneity and therapy resistance are severely dysregulated programmed cell death pathways. Glioblastomas recapitulate many neurodevelopmental and neural injury responses; in addition, glioblastoma cells are composed of multiple different transformed versions of CNS cell types. To obtain a greater understanding of the features underlying cell death regulation in glioblastoma, it is important to understand the control of cell death within the healthy CNS during homeostatic and neurodegenerative conditions. Herein, we review apoptotic control within neural stem cells, astrocytes, oligodendrocytes and neurons and compare them to glioblastoma apoptotic control. Specific focus is paid to the Inhibitor of Apoptosis proteins, which play key roles in neuroinflammation, CNS cell survival and gliomagenesis. This review will help in understanding glioblastoma as a transformed version of a heterogeneous organ composed of multiple varied cell types performing different functions and possessing different means of apoptotic control. Further, this review will help in developing more glioblastoma-specific treatment approaches and will better inform treatments looking at more direct brain delivery of therapeutic agents.