CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma

Liu, Lu; Hui, Ruting; Zeng, Tianyang; Yang, Xuetao; Wu, Qingchen; Yang, Tao

doi:10.2147/ijgm.s355889

Cited by 3 publications

(4 citation statements)

References 38 publications

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“…Our data are also supported by a recent study by Liu, L et al that employed publicly available datasets to identify correlations between CUL4B and the PM tumor microenvironment. The study employed gene expression data from the TCGA and GEO databases to demonstrate significant correlations between CUL4B expression and clinical outcomes and immune cell infiltration [20]. Confirming our previous data, the analyses showed that CUL4B expression was elevated in PM tumor tissue compared to normal pleura, and high CUL4B expression was associated with short the progressionfree survival of PM patient cohorts.…”

Section: Discussionsupporting

confidence: 63%

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma

Kreienbühl,

Changkhong,

Orlowski

et al. 2023

IJMS

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We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.

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Section: Discussionsupporting

confidence: 63%

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma

Kreienbühl,

Changkhong,

Orlowski

et al. 2023

IJMS

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“…Nevertheless, the exact mechanism by which IGFBP3 is engaged in all this is still puzzling. Reportedly, there was a significant correlation between CUL4B and IGFBP3 in mesothelioma [ 14 ]. Besides, CUL4B deficiency affects immune cell function and infiltration [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

Zhao,

Wang,

et al. 2024

Cancer Cell Int

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Background Glioblastoma (GBM) characterized by immune escape is the most malignant primary brain tumors, which has strong immunosuppressive effect. Programmed death ligand-1 (PD-L1) is a recognized immunosuppressive member on the surface of tumor cells, and plays a crucial role in immune evasion of tumors. Actually, little is known about the regulation of PD-L1 expression in GBM. Insulin-like growth factor binding protein 3 (IGFBP3) is upregulated in GBM and is related to poor patient prognosis. However, it remains unclear whether IGFBP3 plays a role in the regulation of PD-L1 expression in GBM. Methods The role of IGFBP3 in the glioma immune microenvironment was investigated using the CIBERSORT algorithm. The correlation between IGFBP3 and PD-L1 expression was analyzed using TCGA and CGGA databases. QRT-PCR, immunoblotting and RNA-seq were used to examine the regulatory effect of IGFBP3 on PD-L1 expression. Co-culture assay, cell counting kit (CCK-8), qRT-PCR, ELISA and flow cytometry were performed to explore the function of IGFBP3 in inducing immunosuppression. The biological role of IGFBP3 was verified using immunohistochemical, immunofluorescence and mice orthotopic tumor model. Results In this study, we analyzed immune cells infiltration in gliomas and found that IGFBP3 may be associated with an immunosuppressive microenvironment. Then, by analyzing TCGA and CGGA databases, our results showed that IGFBP3 and PD-L1 expression were positively correlated in GBM patients, but not in LGG patients. In vitro experiments conducted on different GBM cell lines revealed that the overexpression of IGFBP3 led to an increase in PD-L1 expression, which was reversible upon knockdown IGFBP3. Mechanistically, IGFBP3 activated the JAK2/STAT3 signaling pathway, leading to an increase in PD-L1 expression. Additionally, co-culture experiments results showed IGFBP3 overexpression induced upregulation of PD-L1 expression promoted apoptosis in Jurkat cells, and this effect was blocked by IGFBP3 antibody and PDL-1 inhibitors. Importantly, in vivo experiments targeting IGFBP3 suppressed tumor growth and significantly prolonged the survival of mice. Conclusions This research demonstrated IGFBP3 is a novel regulator for PD-L1 expression in GBM, and identified a new mechanism by which IGFBP3 regulates immune evasion through PD-L1, suggesting that IGFBP3 may be a potential novel target for GBM therapy.

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“…The genes encoding a family of genes in this family of proteins form a complex that acts as an intracellular specific linker substrate for enzymatic activity, with a RING‐finger protein polygenic protein 10 . The staining components of several regulators (including quality permitting DNA replication factor 1 in e) 11 …”

Section: Introductionmentioning

confidence: 99%

“… 10 The staining components of several regulators (including quality permitting DNA replication factor 1 in e). 11 …”

Section: Introductionmentioning

confidence: 99%

CUL4B increases platinum‐based drug resistance in colorectal cancer through EMT: A study in its mechanism

Luo

Wang

et al. 2022

J Cellular Molecular Medi

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Colorectal cancer (CRC) is globally the third most common and the second deadliest tumour in humans regardless of gender. 1 Some of its fatality can be attributed to its strong ties to genetics and environmental effects. In the past years, incidence and mortality of CRC has been steadily decreasing, partly accreditable to the health-conscious society's increased tumour surveillance and better treatment. 2 The typical CRC begins as an adenomatous polyp in the normal colonic epithelium as it accumulates mutations in known targetable oncogenes, tumour suppressor genes, and genes related to DNA repair. 3 CRC is subclassified into stage 0, stage I, stage II, stage III, and stage IV depending on its depth of invasion, lymph node involvement, and metastasis, with stage 0 being the earliest, while stage IV signifying the most advanced. The prognosis of CRC is directly related to its staging, as well as the treatment available. As a rule of thumb, stage 0 is curable through operation, stage II requires a combination of adjuvant chemotherapy or radiotherapy along with a wider surgical resection to improve the success rate of treatment. 4 Chemotherapy plays a pivotal role in CRC treatment regimens, specifically platinumbased chemotherapeutic agents. 5 Presently, there are many studies on the drug resistance in these platinum-based agents for CRC, including fields such as DNA repair, tumour stem cells and epithelialmesenchymal transition (EMT), tumour microenvironment, etc. 6

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CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma

Cited by 3 publications

References 38 publications

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma

Cullin 4B Ubiquitin Ligase Is Important for Cell Survival and Regulates TGF-β1 Expression in Pleural Mesothelioma

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

CUL4B increases platinum‐based drug resistance in colorectal cancer through EMT: A study in its mechanism

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