Research

15 pages, 2185 KiB

Open AccessArticle

Augmenting the Antitumor Efficacy of Natural Killer Cells via SynNotch Receptor Engineering for Targeted IL-12 Secretion

by Ali Ahmadnia, Saeed Mohammadi, Ahad Yamchi, Mohamad Reza Kalani, Touraj Farazmandfar, Ayyoub Khosravi and Ali Memarian

Curr. Issues Mol. Biol. 2024, 46(4), 2931-2945; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb46040183 - 28 Mar 2024

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Abstract

Natural killer (NK) cells are crucial components of innate immunity, known for their potent tumor surveillance abilities. Chimeric antigen receptors (CARs) have shown promise in cancer targeting, but optimizing CAR designs for NK cell functionality remains challenging. CAR-NK cells have gained attention for [...] Read more.

Natural killer (NK) cells are crucial components of innate immunity, known for their potent tumor surveillance abilities. Chimeric antigen receptors (CARs) have shown promise in cancer targeting, but optimizing CAR designs for NK cell functionality remains challenging. CAR-NK cells have gained attention for their potential to reduce side effects and enable scalable production in cancer immunotherapy. This study aimed to enhance NK cell anti-tumor activity by incorporating PD1-synthetic Notch (synNotch) receptors. A chimeric receptor was designed using UniProt database sequences, and 3D structure models were generated for optimization. Lentiviral transduction was used to introduce PD1-Syn receptors into NK cells. The expression of PD1-Syn receptors on NK cell surfaces was assessed. Engineered NK cells were co-cultured with PDL1+ breast cancer cells to evaluate their cytotoxic activity and ability to produce interleukin-12 (IL-12) and interferon-gamma (IFNγ) upon interaction with the target cells. This study successfully expressed the PD1-Syn receptors on NK cells. CAR-NK cells secreted IL-12 and exhibited target-dependent IFNγ production when engaging PDL1+ cells. Their cytotoxic activity was significantly enhanced in a target-dependent manner. This study demonstrates the potential of synNotch receptor-engineered NK cells in enhancing anti-tumor responses, especially in breast cancer cases with high PDL1 expression. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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21 pages, 8955 KiB

Open AccessArticle

Development of the RF-GSEA Method for Identifying Disulfidptosis-Related Genes and Application in Hepatocellular Carcinoma

by Linghao Ni, Qian Yu, Ruijia You, Chen Chen and Bin Peng

Curr. Issues Mol. Biol. 2023, 45(12), 9450-9470; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45120593 - 24 Nov 2023

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Abstract

Disulfidptosis is a newly discovered cellular programmed cell death mode. Presently, a considerable number of genes related to disulfidptosis remain undiscovered, and its significance in hepatocellular carcinoma remains unrevealed. We have developed a powerful analytical method called RF-GSEA for identifying potential genes associated [...] Read more.

Disulfidptosis is a newly discovered cellular programmed cell death mode. Presently, a considerable number of genes related to disulfidptosis remain undiscovered, and its significance in hepatocellular carcinoma remains unrevealed. We have developed a powerful analytical method called RF-GSEA for identifying potential genes associated with disulfidptosis. This method draws inspiration from gene regulation networks and graph theory, and it is implemented through a combination of random forest regression model and Gene Set Enrichment Analysis. Subsequently, to validate the practical application value of this method, we applied it to hepatocellular carcinoma. Based on the RF-GSEA method, we developed a disulfidptosis-related signature. Lastly, we looked into how the disulfidptosis-related signature is connected to HCC prognosis, the tumor microenvironment, the effectiveness of immunotherapy, and the sensitivity of chemotherapy drugs. The RF-GSEA method identified a total of 220 disulfidptosis-related genes, from which 7 were selected to construct the disulfidptosis-related signature. The high-disulfidptosis-related score group had a worse prognosis compared to the low-disulfidptosis-related score group and showed lower infiltration levels of immune-promoting cells. The high-disulfidptosis-related score group had a higher likelihood of benefiting from immunotherapy compared to the low-disulfidptosis-related score group. The RF-GSEA method is a powerful tool for identifying disulfidptosis-related genes. The disulfidptosis-related signature effectively predicts HCC prognosis, immunotherapy response, and drug sensitivity. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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14 pages, 5207 KiB

Open AccessArticle

Fenbendazole Exhibits Differential Anticancer Effects In Vitro and In Vivo in Models of Mouse Lymphoma

by Haebeen Jung, Si-Yeon Kim and Hong-Gu Joo

Curr. Issues Mol. Biol. 2023, 45(11), 8925-8938; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110560 - 08 Nov 2023

Viewed by 4436

Abstract

Fenbendazole (FBZ) has been safely used as an antiparasitic agent in animals for decades, and the anticancer effects of FBZ have been studied through various mechanisms. However, there is a lack of in vivo studies that include lymphoma. Therefore, this study examined the [...] Read more.

Fenbendazole (FBZ) has been safely used as an antiparasitic agent in animals for decades, and the anticancer effects of FBZ have been studied through various mechanisms. However, there is a lack of in vivo studies that include lymphoma. Therefore, this study examined the effects of FBZ on EL-4 cells and a mouse T lymphoma model. FBZ induced G2/M phase arrest in EL-4 cells, resulting in cell death and decreased metabolic activity. However, FBZ had no anticancer effects on an EL-4 mouse lymphoma model in vivo, as evident by rapid weight loss and tumor growth comparable to the control. The FBZ-treated EL-4 cells expressed higher levels of PD-L1 and CD86, which are associated with T cell immunity in the tumor microenvironment (TME), than the controls. Furthermore, the hematoxylin and eosin staining of the FBZ-treated tumor tissues showed a starry sky pattern, which is seen in actively proliferating cancer tissues, and an immunohistochemical analysis revealed a high percentage of immunosuppressive M2 macrophages. These changes in the immune activity in the TME contradict the results of the in vitro experiments, and further studies are needed to determine the detailed mechanisms by which FBZ induces these responses. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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17 pages, 6763 KiB

Open AccessArticle

Validation of a Novel Cuproptosis–Related Prognostic Gene Marker and Differential Expression Associated with Lung Adenocarcinoma

by Tingting Liu and Jianshe Wei

Curr. Issues Mol. Biol. 2023, 45(10), 8502-8518; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45100536 - 22 Oct 2023

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Abstract

Background: Cuproptosis induction is seen as a promising alternative for immunotherapies and targeted therapies in breast cancer. The objective of this research was to examine the prognostic and biological importance of cuproptosis-related genes (CRGs) in lung adenocarcinoma (LUAD). Methods: The following methods were [...] Read more.

Background: Cuproptosis induction is seen as a promising alternative for immunotherapies and targeted therapies in breast cancer. The objective of this research was to examine the prognostic and biological importance of cuproptosis-related genes (CRGs) in lung adenocarcinoma (LUAD). Methods: The following methods were used: GSE10072 dataset and TCGA database analysis, differential expression analysis of CRGs, and biological function (BP) and signaling pathway enrichment analysis, prognostic analysis and clinical analysis of CRGs, construction of the prognostic signature and RNA modified genes and miRNA analysis of CRGs in LUAD, immunoinfiltration analysis and immunohistochemical staining of DβH, UBE2D3, SOD1, UBE2D1 and LOXL2. Results: AOC1, ATOX1, CCL8, CCS, COX11, CP, LOXL2, MAP2K2, PDK1, SCO2, SOD1, UBE2D1, UBE2D3 and VEGFA showed significantly higher expression, while ATP7B, DβH, PDE3B, SLC31A2, UBE2D2, UBE2D4 and ULK2 showed lower expression in LUAD tissues than normal tissues. We also found that ATP7B (4%), AOC1 (3%) PDE3B (2%), DβH (2%), CP (1%), ULK2 (1%), PDK1 (1%), LOXL2 (1%) and UBE2D3 (1%) showed higher mutation frequencies. The univariate Cox analysis was used to identify CRGs that have prognostic value. It identified 21 genes that showed significant prognostic value, containing DβH, UBE2D3, SOD1, UBE2D1 and LOXL2. Patients with DβH up–expression have a longer survival time and patients with UBE2D3, SOD1, UBE2D1 and LOXL2 down–expression also have a longer survival time. hsa–miR–29c–3p, hsa–miR–29a–3p, hsa–miR–181c–5p, hsa–miR–1245a, etc., play an important role in the miRNA regulatory network, and in LUAD, miR–29a, miR–29c and miR–181c high expression survival was longer, and miR–1245a low expression survival was longer. We also performed an analysis to examine the relationships between DβH, LOXL2, SOD1, UBE2D1 and UBE2D3 and immune infiltration in LUAD, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils and DCs. Conclusion: DβH, UBE2D3, SOD1, UBE2D1, and LOXL2 are potential candidates implicated in LUAD and can be further explored for their application as diagnostic, prognostic, and therapeutic biomarkers for LUAD. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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24 pages, 34881 KiB

Open AccessArticle

Small Leucine-Rich Proteoglycan PODNL1 Identified as a Potential Tumor Matrix-Mediated Biomarker for Prognosis and Immunotherapy in a Pan-Cancer Setting

by Geyang Dai, Yue Sun, Rui Wei and Ling Xi

Curr. Issues Mol. Biol. 2023, 45(7), 6116-6139; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45070386 - 22 Jul 2023

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Abstract

The podocan-like protein 1 (PODNL1), an important member of the small leucine-rich proteoglycans (SLRP) family, is a crucial component of the tumor microenvironment (TME). But its prognostic values and the role in the TME have not been systematically estimated in a pan-cancer setting. [...] Read more.

The podocan-like protein 1 (PODNL1), an important member of the small leucine-rich proteoglycans (SLRP) family, is a crucial component of the tumor microenvironment (TME). But its prognostic values and the role in the TME have not been systematically estimated in a pan-cancer setting. Targeting PODNL1, a systematic exploration into the TCGA datasets, reconciling with the analyses of single-cell transcriptomes and immunotherapeutic cohorts in cancers, and validation by tissue microarray-based multiplex immunofluorescence staining was performed. PODNL1 was significantly correlated with the poor prognosis and immunotherapeutic responses in various cancers. In-depth demonstration of molecular mechanisms indicated that PODNL1 expressions were notably positively correlated with cancer-associated fibroblast (CAF) infiltration levels in 33 types of cancers. It also positively correlated with the pan-fibroblast TGF-β response signature score, and the hallmarks including TGF-β, TNF-α, inflammatory response, apical junction, epithelial–mesenchymal transition and hedgehog in pan-cancer. Furthermore, high PODNL1 expressions were positively related with the regulation of tumor-promoting TGF-β signaling through downregulating SMAD2/3:4 heterotrimer regulations transcription and up-regulating the pathway restricted SMAD protein phosphorylation. Single-cell transcriptome analyses and immunofluorescence validations indicated that PODNL1 was predominantly expressed in the cancer cells and CAFs in various cancers. Additionally, the heterogeneity of cancer genotype–phenotype cross-talking was also observed associated with PODNL1. Our systematic study indicates that PODNL1 plays an important role in the complex regulation network of tumor progression, and lays a foundation for further exploration to develop PODNL1 as a valuable matrix-mediated biomarker for cancer immunotherapy and prognosis in a pan-cancer setting. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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Review

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18 pages, 2299 KiB

Open AccessReview

Biological Roles and Pathogenic Mechanisms of LncRNA MIR4435-2HG in Cancer: A Comprehensive Review

by Zhou Chen, Defeng Guan, Qiangping Zhu, Zhengfeng Wang, Fangfang Han and Wence Zhou

Curr. Issues Mol. Biol. 2023, 45(11), 8864-8881; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110556 - 04 Nov 2023

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Abstract

The long non-coding RNA MIR4435-2HG has been confirmed to play a crucial regulatory role in various types of tumors. As a novel type of non-coding RNA, MIR4435-2HG plays a key role in regulating the expression of tumor-related genes, interfering with cellular signaling pathways, [...] Read more.

The long non-coding RNA MIR4435-2HG has been confirmed to play a crucial regulatory role in various types of tumors. As a novel type of non-coding RNA, MIR4435-2HG plays a key role in regulating the expression of tumor-related genes, interfering with cellular signaling pathways, and affecting tumor immune evasion. Its unique structure allows it to regulate the expression of various tumor-related genes through different pathways, participating in the regulation of tumor signaling pathways, such as regulating the expression of oncogenes and tumor suppressor genes, influencing the biological behaviors of proliferation, metastasis, and apoptosis in tumors. Numerous studies have found a high expression of MIR4435-2HG in various tumor tissues, closely related to the clinical pathological characteristics of tumors, such as staging, lymph node metastasis and prognosis. Some studies have discovered that MIR4435-2HG can regulate the sensitivity of tumor cells to chemotherapy drugs, affecting tumor cell drug resistance. This provides new insights into overcoming tumor drug resistance by regulating MIR4435-2HG. Therefore, studying its molecular mechanisms, expression regulation, and its relationship with the clinical features of tumors is of great significance for revealing the mechanisms of tumor occurrence and developing new therapeutic targets. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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17 pages, 1716 KiB

Open AccessReview

Autophagy Modulation and Its Implications on Glioblastoma Treatment

by Johnny Chen, Andrea Salinas Rodriguez, Maximiliano Arath Morales and Xiaoqian Fang

Curr. Issues Mol. Biol. 2023, 45(11), 8687-8703; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110546 - 29 Oct 2023

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Abstract

Autophagy is a vital cellular process that functions to degrade and recycle damaged organelles into basic metabolites. This allows a cell to adapt to a diverse range of challenging conditions. Autophagy assists in maintaining homeostasis, and it is tightly regulated by the cell. [...] Read more.

Autophagy is a vital cellular process that functions to degrade and recycle damaged organelles into basic metabolites. This allows a cell to adapt to a diverse range of challenging conditions. Autophagy assists in maintaining homeostasis, and it is tightly regulated by the cell. The disruption of autophagy has been associated with many diseases, such as neurodegenerative disorders and cancer. This review will center its discussion on providing an in-depth analysis of the current molecular understanding of autophagy and its relevance to brain tumors. We will delve into the current literature regarding the role of autophagy in glioma pathogenesis by exploring the major pathways of JAK2/STAT3 and PI3K/AKT/mTOR and summarizing the current therapeutic interventions and strategies for glioma treatment. These treatments will be evaluated on their potential for autophagy induction and the challenges associated with their utilization. By understanding the mechanism of autophagy, clinical applications for future therapeutics in treating gliomas can be better targeted. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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35 pages, 959 KiB

Open AccessReview

Interactions between the DNA Damage Response and the Telomere Complex in Carcinogenesis: A Hypothesis

by Antonio Torres-Montaner

Curr. Issues Mol. Biol. 2023, 45(9), 7582-7616; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45090478 - 19 Sep 2023

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Abstract

Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage [...] Read more.

Contrary to what was once thought, direct cancer originating from normal stem cells seems to be extremely rare. This is consistent with a preneoplastic period of telomere length reduction/damage in committed cells that becomes stabilized in transformation. Multiple observations suggest that telomere damage is an obligatory step preceding its stabilization. During tissue turnover, the telomeres of cells undergoing differentiation can be damaged as a consequence of defective DNA repair caused by endogenous or exogenous agents. This may result in the emergence of new mechanism of telomere maintenance which is the final outcome of DNA damage and the initial signal that triggers malignant transformation. Instead, transformation of stem cells is directly induced by primary derangement of telomere maintenance mechanisms. The newly modified telomere complex may promote survival of cancer stem cells, independently of telomere maintenance. An inherent resistance of stem cells to transformation may be linked to specific, robust mechanisms that help maintain telomere integrity. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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Other

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8 pages, 15905 KiB

Open AccessBrief Report

Modelling 3D Tumour Microenvironment In Vivo: A Tool to Predict Cancer Fate

by Johanna Marines, Francesca Lorenzini, Karima Kissa and Laura Fontenille

Curr. Issues Mol. Biol. 2023, 45(11), 9076-9083; https://0-doi-org.brum.beds.ac.uk/10.3390/cimb45110569 - 14 Nov 2023

Viewed by 876

Abstract

Recently, many studies demonstrated the fundamental role of the tumour microenvironment (TME) in cancer progression. Here, we describe a method to visualize in 3D the behaviour of tumours in zebrafish embryos. We highlight two major actors of the TME, macrophages and vessels. This [...] Read more.

Recently, many studies demonstrated the fundamental role of the tumour microenvironment (TME) in cancer progression. Here, we describe a method to visualize in 3D the behaviour of tumours in zebrafish embryos. We highlight two major actors of the TME, macrophages and vessels. This valuable tool is transposable to Patient-Derived Xenograft imaging in order to predict the fate of malignant tumours according to the dynamics of their TME. Full article

(This article belongs to the Special Issue Targeting Tumor Microenvironment for Cancer Therapy, 2nd Edition)

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