Cell Proliferation最新文献

Y. Wang, J. H. Li, Z. Q. Wang, J. Li, Z. Wang, Y. Liu, T. Wang, M. Zhang, C. Xia, F. Zhang, D. Huang, L. Zhang, Y. Zhao, L. Liu, Y. Zhu, H. Qi, X. Zhu, W. Qian, F. Hu and J. Wang, “Comparison of Seven CD19 CAR Designs in Engineering NK Cells for Enhancing Anti-Tumour Activity,” Cell Proliferation 57, no. 11 (2024): e13683. https://doi.org/10.1111/cpr.13683.

In Figure 1A, the promoters of the SFG vector in structure schematic diagrams were mistakenly labelled as “α-globin”. The errors do not affect the rest of the article. The incorrect version is shown below:

The corrected Figure 1 and accompanying legend appear below.

The incorrect Figure:

Corrected Figure:

We apologize for the errors.

CRISPR-Cas9 technology has rapidly advanced as a transformative genome-editing platform, facilitating precise genetic modifications and expanding therapeutic opportunities across various diseases. This review explores recent developments and clinical translations of CRISPR applications in oncology, genetic and neurological disorders, infectious diseases, immunotherapy, diagnostics, and epigenome editing. CRISPR has notably progressed in oncology, where it enables the identification of novel cancer drivers, elucidation of resistance mechanisms, and improvement of immunotherapies through engineered T cells, including PD-1 knockout CAR-T cells. Clinical trials employing CRISPR-edited cells are demonstrating promising results in hematologic malignancies and solid tumours. In genetic disorders, such as hemoglobinopathies and muscular dystrophies, CRISPR-Cas9 alongside advanced editors like base and prime editors show significant potential for correcting pathogenic mutations. This potential was affirmed with the FDA's first approval of a CRISPR-based therapy, Casgevy, for sickle cell disease in 2023. Neurological disorders, including Alzheimer's, ALS, and Huntington's disease, are increasingly targeted by CRISPR approaches for disease modelling and potential therapeutic intervention. In infectious diseases, CRISPR-based diagnostics such as SHERLOCK and DETECTR provide rapid, sensitive nucleic acid detection, particularly valuable in pathogen outbreaks like SARS-CoV-2. Therapeutically, CRISPR systems target viral and bacterial genomes, offering novel treatment modalities. Additionally, CRISPR-mediated epigenome editing enables precise regulation of gene expression, expanding therapeutic possibilities. Despite these advances, significant challenges remain, including off-target effects, delivery methodologies, immune responses, and long-term genomic safety concerns. Future improvements in editor precision, innovative delivery platforms, and enhanced safety assessments will be essential to fully integrate CRISPR-based interventions into standard clinical practice, significantly advancing personalised medicine.

Osteosarcoma (OS) is a primary bone tumour that occurs mostly in adolescents and is associated with a high degree of malignancy, early metastasis, and poor prognosis. Pyropheophorbide-a methyl ester-Photodynamic therapy (MPPa-PDT) is a new approach for the clinical treatment of osteosarcoma that develops after surgery and radiotherapy; however, the presence of MPPa-PDT resistance in osteosarcoma greatly limits its efficacy. In this study, we found that Rho-associated coiled-coil containing protein kinase 2 (ROCK2) expression increased in osteosarcoma cells after MPPa-PDT treatment. ROCK2 inhibition results in osteosarcoma sensitivity to MPPa-PDT and is accompanied by a decrease in cellular autophagy levels. Rescue experiments further showed that ROCK2 mediates MPPa-PDT resistance in osteosarcoma by regulating autophagy. Mechanistic studies have shown that ROCK2 mediates autophagy in osteosarcoma cells by regulating the Hippo signalling pathway. ROCK2 overexpression resulted in increased levels of the ROCK2-Salvador homology 1 (SAV1) complex and decreased levels of the mammalian STE20-like protein kinase 1 (MST1)-SAV1 complex, thereby inhibiting activation of the Hippo pathway, which in turn led to osteosarcoma MPPa-PDT resistance by regulating cellular autophagy. ROCK2 competes with MST1 for binding to the aa 28-198 region of SAV1. We also confirmed from a clinical perspective that ROCK2 is an independent prognostic factor in patients with osteosarcoma, is associated with worse patient prognosis, and correlates with the Hippo pathway. Targeted inhibition of ROCK2 by screening for J059-0149 increases the sensitivity of osteosarcoma to MPPa-PDT. In conclusion, our study establishes a novel mechanism to reverse MPPa-PDT resistance in osteosarcoma by targeting ROCK2-mediated autophagy, providing new targets and research ideas for the clinical treatment of osteosarcoma MPPa-PDT resistance.

Endocrine resistance is a leading cause of mortality in oestrogen receptor-positive and human epidermal growth factor receptor 2-negative (ER+HER2-) breast cancer (BC), highlighting the urgent need to understand its underlying molecular mechanisms and identify potentially resistant patients for effective management. In this study, we constructed endocrine-resistant cell lines through long-term oestrogen deprivation and identified differentially expressed genes (DEGs) via transcriptome analysis. Key endocrine-resistant genes were defined through Cox regression analysis. Our findings revealed that the genes CLEC3A, PCDH10, and ST3GAL1 were significantly upregulated in endocrine-resistant cells and serve as independent prognostic factors for ER+HER2- BC patients. We developed an endocrine resistance score (ERS), and a nomogram model incorporating ERS demonstrated robust predictive capabilities for patient prognosis. Single-cell RNA sequencing analysis demonstrated that the ERS and the three core genes constituting the ERS were significantly upregulated in tissue specimens from patients with resistance to endocrine neoadjuvant therapy. Additionally, knocking down CLEC3A, PCDH10, and ST3GAL1 led to reduced malignancy progression in endocrine-resistant BC cells. Mechanistic studies revealed that CLEC3A promotes endocrine resistance by upregulating the PI3K-AKT pathway. This study suggests that CLEC3A, PCDH10, and ST3GAL1 are associated with endocrine resistance and can reflect the prognosis of ER+HER2- BC patients receiving endocrine therapy, providing potential therapeutic targets and a valuable prognostic indicator for clinicians.

Melasma is a recurrent and treatment-resistant hyperpigmentation disorder characterized by a complex and multifactorial pathogenesis. However, the lack of a stable and reliable animal model has hindered systematic investigations into its onset and progression. In this study, we established a melasma-like model in C57BL/6J mice by combining broadband UVB irradiation, intramuscular progesterone administration, and induced emotional stress. The affected skin areas exhibited irregular, brown hyperpigmented patches. Histopathological analysis revealed an accumulation of melanin granules in the epidermis and superficial dermis, elevated levels of tyrosinase (TYR) in both skin and plasma, systemic oxidative stress imbalance, and reduced autophagic activity in the lesional skin. Furthermore, this model displayed distinct differences from a UV-induced post-inflammatory hyperpigmentation (PIH) model. Notably, the melasma-like mice responded to tranexamic acid treatment in a manner that closely resembled clinical outcomes observed in human patients. Collectively, these findings establish a stable, reproducible, and clinically relevant mouse model of melasma, providing a valuable platform for future research into its pathogenesis and treatment.

The cover image is based on the article Intelligent Manufacturing for Osteoarthritis Organoids by Xukun Lyu et al., https://doi.org/10.1111/cpr.70043.

Understanding the structural and functional organisation of brain networks is a fundamental objective in neuroscience, with three-dimensional (3D) reconstruction of single-neuron morphology serving as a critical foundation. The Golgi staining method, which enables random neuronal labeling and provides high-contrast signals in both optical and X-ray microscopy, remains a valuable tool for morphological analysis. However, its widespread application in large-scale neuronal reconstructions is hindered by signal discontinuities in neuronal branches, high-density labeling, and complex background interference. While automated reconstruction methods perform well in sparsely labelled and morphologically simple neuronal populations, their effectiveness is limited in Golgi-stained samples. Here we develop a semi-automated single-neuron reconstruction method for Golgi-stained mouse brain neurons (SNR-Golgi). By integrating three key technical modules—background denoising, single-neuron extraction, and branch repair—SNR-Golgi significantly enhances the accuracy and completeness of neuronal reconstruction. In fluorescence micro-optical sectioning tomography (fMOST) datasets, SNR-Golgi demonstrated superior performance in neuronal reconstruction within the mouse somatosensory cortex, achieving a 30% increase in reconstructed branch count, a 76% improvement in total branch length, and a 3.7-fold increase in axonal length. Additionally, in synchrotron-based X-ray imaging datasets, SNR-Golgi enabled submicron-resolution 3D reconstruction of single neurons. These results demonstrate that SNR-Golgi effectively addresses the complexity of Golgi-stained samples and provides robust technical support for the structural analysis of brain neurons across various imaging modalities.

Benign prostatic hyperplasia (BPH) is a common condition in older men, with its prevalence increasing as age advances. Chronic inflammation orchestrates oxidative stress to exacerbate BPH. YAP1, which regulates organ size, cellular homeostasis, and tissue fibrosis, can be activated by ROCK1. Given the urgent clinical need for more effective therapies, this study explored whether targeting the ROCK1/YAP1 axis could mitigate BPH progression. Here, rats received in situ adeno-associated virus (AAV) injection to induce prostate-specific YAP1 overexpression. An inflammation-associated experimental autoimmune prostatitis (EAP) model was established by prostate antigen immunisation, followed by treatment with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Cell models were treated with specific inhibitors to confirm the critical role of YAP1 in modulating mitochondrial function. As a result, YAP1 overexpression was sufficient to induce a pathological BPH phenotype. Specifically, YAP1 activated the inflammatory cascade to provoke an immune response, disrupted proliferation/apoptosis balance to induce tissue hyperplasia, triggered epithelial-mesenchymal transition (EMT) and reactive stroma to drive fibrosis, and promoted NOX4/ROS generation and antioxidant depletion to cause oxidative stress. The inflammation-induced experimental autoimmune prostatitis (EAP) model also presented analogous BPH lesions, which were significantly alleviated when treated with ROCK1 inhibitor fasudil and YAP1 inhibitor verteporfin. Mechanistically, YAP1 activation under inflammatory conditions suppressed SIRT1 expression, thereby exacerbating oxidative stress through the disruption of DRP1/MFN2-mediated mitochondrial dynamics. Overall, inflammation-driven activation of the ROCK1/YAP1 axis aggravates oxidative stress, promoting BPH hyperplasia and fibrosis by impairing SIRT1-regulated mitochondrial dynamics. These findings provide a preclinical rationale for developing ROCK1 or YAP1 inhibitors as targeted therapies for BPH patients with chronic inflammation.

Mitochondrial stress-induced mitophagy plays a critical role to maintain cellular homeostasis; however, in cancer cells, this process may also contribute to drug resistance. Our previous work identified CDK12 as a critical regulator of prostate cancer (PCa) cell survival under sustained enzalutamide exposure, though the precise mechanism remains to be elucidated. In this study, we hypothesize that CDK12 plays a key role in mitophagy regulation under mitochondrial stress, potentially modulating PCa cell resistance to enzalutamide, the first-line clinical medication in PCa therapy. Utilising multiple in vitro PCa cell models, we demonstrate that both CDK12 knockdown and pharmacological inhibition with THZ531 impaired mitophagy following treatment with enzalutamide and mitophagy inducer CCCP. Mechanistically, our finding reveal that CDK12 inhibition disrupts FOXO3-induced BNIP3 transcription, thereby preventing receptor-mediated mitophagy and sensitising PCa cells to enzalutamide. This study identifies the CDK12-FOXO3-BNIP3 pathway as a novel regulatory mechanism governing mitophagy under mitochondrial stress. Importantly, these results underscore CDK12's role in preserving mitochondrial function and promoting PCa cell survival during enzalutamide treatment. These findings highlight the therapeutic potential of targeting the CDK12-BNIP3-mitophagy axis in combination with antiandrogen therapies, offering a promising strategy to overcome drug resistance in PCa and improve clinical outcomes.

Aminoglycoside antibiotics are essential in managing many life-threatening diseases. However, their derivatives, such as neomycin, are associated with severe side effects such as persistent sensorineural hearing loss. Therefore, it is essential to elucidate the molecular and biochemical mechanisms of aminoglycoside-induced ototoxicity and identify targets for alleviating ototoxic injury. Here, we provide a detailed cochlear cell atlas of neomycin-induced acute and chronic ototoxicity-related changes through single-nucleus RNA sequencing profiling. Utilising this cochlear cell atlas, we used the Augur and scDist algorithms to evaluate cell-type-specific susceptibility to neomycin injury. We observed aberrant expression of X-linked inhibitor of apoptosis (Xiap)–associated factor 1 (Xaf1) in neomycin-exposed cochleae using the cochlear cell atlas, and we identified a novel role for Xaf1 in facilitating PANoptosis through overexpression and knockdown assays in vitro. Finally, we assessed the protective role of Xaf1 against neomycin-induced ototoxicity by Xaf1 knockdown in cochlear hair cells using adeno-associated virus-based gene delivery. Mechanistically, Xaf1 orchestrates PANoptosis activation through direct interaction with and transcriptional regulation of ZBP1, establishing its hierarchical position upstream in the signalling cascade. This study presents detailed cochlear cellular maps of neomycin-induced ototoxicity and serves as a valuable resource for identifying transcriptome-wide disease-driving perturbations at the single-cell level. More importantly, we identified Xaf1 as a critical target for modulating the PANoptosis pathway, offering a promising treatment strategy for aminoglycoside-induced ototoxicity.