Translational Oncology最新文献

CLL1 Chimeric antigen receptor T-cell (CAR-T) therapy, as a promising immunotherapeutic approach, has demonstrated its potential to enhance the prognosis of patients diagnosed with acute myeloid leukemia (AML). However, due to the overexpression of CLL1 on neutrophils, CAR-T cells not only eliminated tumor cells but also eradicated neutrophils simultaneously, resulting in severe granulocytopenia and subsequent infections. Considering the distinct expression levels of CD15/CD16 on neutrophils and AML blasts, we have devised novel modified CD15 /CD16-CLL1 iCAR structures incorporating diverse inhibitory elements. Through extensive screening of structural optimization, we have successfully identified CD16-CLL1 iCAR-T cells that combine PD1 and 2B4 blockade, as well as a single VHH fragment replacing the entire CD16 scFv recognition domain. These modified cells demonstrate enhanced cytotoxicity against blasts while minimizing neutrophil elimination. Furthermore, their functionality has been effectively validated through both in vitro and in vivo experiments. In conclusion, we have successfully engineered innovative CD16-CLL1 iCAR-T cells, which preserves the cytotoxicity against tumor cells while preventing elimination of neutrophils, thereby significantly reducing the incidence of granulocytopenia during CAR-T therapy. Furthermore, our future objectives encompass the meticulous validation of both the efficacy and safety profile of this groundbreaking CAR-T therapy in clinical trials, as well as a comprehensive assessment of its potential to enhance the prognosis of patients diagnosed with AML.

Ferroptosis is a novel type of programmed cell death caused by excessive iron-dependent lipid peroxidation. According to various studies, there may be a link between ferroptosis and lipid metabolism. However, few studies have been reported on the lipid metabolism of ferroptosis in acute myeloid leukemia (AML). Here, we analyzed the relationship between lipid metabolism and ferroptosis in AML cells to explore new clinical treatment strategies. This study found that 12 fatty acids were significantly changed in acute myeloid leukemia cell ferroptosis, including dihomo-γ-linolenic acid (DGLA), arachidonic acid (AA), docosahexaenoic acid (DHA), etc. Exogenous DGLA substantially increases the sensitivity to ferroptosis and induces ferroptosis alone in AML cells. In addition, acyl-CoA synthetase long-chain family member 4 (ACSL4) knockout significantly inhibited DGLA-induced AML cells ferroptosis, and ACSL4 regulates DGLA-associated lipid synthesis to affect the sensitivity of AML cells to ferroptosis. Collectively, our studies indicate that a DGLA-enriched diet significantly restricted the growth of leukemia cells as well as induced ferroptosis in vivo.

Molecular regulatory mechanism of MAGI2-AS3 in HNSCC is not yet mature.In this study, we analyzed the methylation level of MAGI2-AS3 promoter and its downstream miR-31-5p/AR axis by bioinformatics methods. qRT-PCR was used to detect the mRNA expression level of each gene, and western blot was used to detect the expression level of AR proteins in tissues and cells. CCK-8, colony formation, wound healing, and cellular invasion assays were used to detect the HNSCC cell proliferation, migration, and invasion. Dual luciferase and RIP assays were performed to validate the binding relationship between genes. The effect of MAGI2-AS3 on HNSCC progression was verified in nude mice in vivo. The low expression of MAGI2-AS3 in HNSCC was caused by hypermethylation of MAGI2-AS3, which could regulate the target of miR-31-5p by sponge adsorption of miR-31-5p, and miR-31-5p could inhibit the expression of AR by directly targeting AR. Thus, MAGI2-AS3 could inhibit the proliferation, migration, and invasion of HNSCC through the miR-31-5p/AR axis. This provided a theoretical basis that MAGI2-AS3 was a potential therapeutic target for HNSCC.

Introduction: Laryngeal cancer (LC) presents a significant health challenge globally, with smoking being a major risk factor. Interestingly, LC incidence in females is significantly lower than in males; however, female smokers are more likely to develop Reinke edema (RE) than LC. This study sought to investigate whether autophagy, a major mechanism for RE development, acts as a defense mechanism in laryngeal tissue against cigarette exposure and suppresses LC development in females who smoke.

Methods: This study analyzed the National Health Insurance Service (NHIS) data of South Korea to explore sex differences in LC incidence and clinical outcomes. Protein expression was compared between tissues from LC and RE patients. The changes in autophagy-related markers were analyzed after exposure to human vocal fold fibroblast (hVFF) and cigarette smoke extract (CSE). In addition, to explore the relationship between the level of autophagy-related gene expression and clinical features, female LC patients were compared with male patients through an analysis of data from The Cancer Genome Atlas (TCGA).

Results: In the NHIS data analyses, male LC patients had an 11 times higher incidence than female patients, even after adjusting for smoking and age. Additionally, female LC patients had significantly better survival rates. RE tissues exhibited increased autophagy-related protein expression compared with LC tissues. hVFFs after CSE exposure demonstrated elevated autophagy markers along with protein expression similar to RE tissue, suggesting autophagy's role in RE development over LC. The TCGA data analysis did not find a significant difference in autophagy-related gene expression, which would explain the favorable female clinical outcomes, between male and female LC patients.

Conclusions: This study implies autophagy activation by cigarette smoke is a crucial mechanism for lower LC incidence and better outcomes in females, highlighting the potential for autophagy-targeted LC prevention and treatment strategies.

Purpose: TRIM6, an E3 ubiquitin ligase with tripartite motif, directly targets protein substrates for degradation through ubiquitination. Studies have shown that TRIM6 plays a significant role in tumor development in various human malignancies. Thus, the aim of this study was to investigate the importance of TRIM6 and its associated mechanism in promoting the progression of glioma.

Methods: The expression of TRIM6 and its prognostic value in glioma patients were collected from the TCGA and CGGA databases. The effects of TRIM6 on glioma were investigated in vitro by CCK8, colony formation, wound healing, and transwell assays. Co-IP and western blot analysis were used to detect the interaction between TRIM6 and FOXO3A. The effects of TRIM6 were verified in vivo in subcutaneously xenograft models, and tumor size, and immunohistochemical changes were observed.

Results: Our analysis of TRIM6 expression in glioma tissues revealed a high level of expression, and the heightened expression of TRIM6 showed a positive correlation with the unfavorable prognosis among glioma/GBM patients. Through loss-of-function and gain-of-function experiments, we observed a profound impact on the proliferation, invasion, and migration abilities of glioma cells both in vitro and in vivo upon deletion of TRIM6. Conversely, the overexpression of TRIM6 intensified the malignant characteristics of glioma. Additionally, our findings revealed a significant interaction between TRIM6 and FOXO3A, wherein TRIM6 contributed to the destabilization of FOXO3A protein by promoting its ubiquitination and subsequent degradation. Experiments conducted in the rescue study affirmed that the promotion of glioma cell proliferation, invasion, and migration is facilitated by TRIM6 through the suppression of FOXO3A protein levels.

Conclusions: These observations imply that the TRIM6-FOXO3A axis could potentially serve as an innovative focus for intervening in glioma.

Objective

Drug resistance greatly limits the therapeutic effect of a drug. This study aimed to explore the role of long noncoding RNA ZFAS1 in Donafenib resistance of hepatocellular carcinoma (HCC) cells.

Methods

The expression of CREB3, ZFAS1, and p65 in HCC cell lines was measured by RT-qPCR and western blotting. After transfection with sh-ZFAS1, sh-CREB3, or sh-CREB3 + oe-p65 in Donafenib-resistent (DR) HCC cell lines, the transfection efficiency was evaluated by RT-qPCR and western blotting. The proliferation and IC₅₀ to Donafenib of HCC cell lines was examined by MTT assay. Cell proliferation and apoptosis were examined by colony formation and flow cytometry assays. Then, the correlation amongst CREB3, ZFAS1, LSD1/CoREST, and p65 was analysed by ChIP, dual-luciferase reporter gene, and RIP assays.

Results

ZFAS1, CREB3, and p65 were upregulated in HepG2-DR and Huh7-DR cells. Silencing of ZFAS1 or CREB3 enhanced the sensitivity of HCC cells to Donafenib, inhibited cell proliferation and IC₅₀, and increased cell apoptosis, which were reversed by p65 overexpression. Mechanistically, CREB3 bound to ZFAS1 promoter to augment ZFAS1 transcriptional expression, and ZFAS1 recruited LSD1/CoREST to the p65 promoter region to decrease H3K4 methylation and elevate p65 transcriptional expression.

Conclusion

CREB3 overexpression contributed to Donafenib resistance in HCC cells by activating the ZFAS1/p65 axis.

Many tumour cells express on their surface proteins of endogenous retroviruses (ERVs) and there are suggestions to use these retroviral antigens as target for anti-tumour vaccines. However, until now there is no convincing data showing that this strategy works, in contrast, there are considerations suggesting that this strategy may be harmful if applied.