UCHL5 promotes Tumorigenesis of Bladder Cancer by Activating AKT/mTOR signaling pathway and targeting c-myc, SLC25A19, and ICAM5.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE211924 | GEO | 2025/08/02
REPOSITORIES: GEO
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Project description:Purpose: To investigate the tumor-promoting role of STIL in bladder cancer. Method: We established the STIL knockout cell line in which the target gene was knocked out by sgRNA. RNA was extracted from cells using trizol reagent(Invitrogen) Result: Through RNA-sequencing analysis of wild-type and STIL-deficient UMUC3 cell lines, the downstream signaling pathways that STIL may be involved in were determined. We found that the PI3K/AKT/mTOR signaling pathway and c-myc were significantly inactivated when STIL was knocked out in bladder cancer. Our RNA-sequencing analysis results showed that the downstream molecules of c-myc (MCM4, HSPD1, EIF2S2, DDX21, DDX18, CBX3, ABCE1) were significantly down-regulated in bladder cancer cells after knockout. Conclusion: STIL enhances the PI3K/AKT/mTOR pathway, which consequently upgraded the expression of c-myc, ultimately promoting the occurrence and progression of bladder cancer C. STIL may suggest potential utility for bladder cancer therapy.
2023-08-01 | GSE211756 | GEO
Project description:UCHL5 promotes Tumorigenesis of Bladder Cancer by Activating AKT/mTOR signaling pathway and targeting c-myc, SLC25A19, and ICAM5.
| PRJNA872911 | ENA
Project description:Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and the development of acquired resistance to PI3K-AKT-mTOR inhibitors remain major challenges for successful patient treatment. Here, we show that MYC activation is a central and clinically relevant mechanism of resistance to mTOR inhibitors (mTORi) in breast cancer. Multi-omic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent focal Myc amplification in tumors that acquire resistance to the mTORi AZD8055. The gained MYC activity was significantly associated with biological processes linked to mTORi response. Specifically, MYC counteracted the translation inhibitory effect induced by mTORi by promoting the translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred resistance to AZD8055 as well as the clinically approved mTORi everolimus, both in mouse models of ILC and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by synergistic growth inhibition using mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant determinant of mTORi resistance that may guide the selection of breast cancer patients for mTOR targeted therapies.
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Project description:Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.
2025-08-14 | GSE287094 | GEO
Project description:Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.
2025-06-07 | GSE269445 | GEO
Project description:Recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with a high unmet need for enhancing immunotherapy given current modest responses. Here, we performed an in vivo CRISPR screen in a HNSCC mouse model to identify immune evasion genes. We identified several epigenetic regulators of immune checkpoint blockade (ICB) response, including the ubiquitin C-terminal hydrolase 5 (UCHL5). Loss of Uchl5 in tumors increased CD8+ T cell infiltration and improved ICB responses. Uchl5 deficiency reduced extracellular matrix (ECM) production and epithelial-mesenchymal-transition (EMT) transcriptional signatures, which contribute to stromal desmoplasia, a histologic finding associated with reduced anti-PD1 response in human HNSCCs. We identified a functional role for COL17A1, a collagen highly and specifically expressed in HNSCC, in Uchl5-mediated immune evasion. Our findings suggest an unappreciated role for UCHL5 in promoting EMT in HNSCC and highlight ECM modulation as a strategy to improve immunotherapy responses.
2025-06-07 | GSE269444 | GEO
Project description:Gastric cancer (GC) is one of the most common malignant cancers in the world. c-Myc, a well-known oncogene, is commonly amplified in many cancers, including gastric cancer. However, it is still not completely understood how c-Myc functions in GC. Here, we generated a stomach-specific c-Myc knock-in mouse model to investigate its role in GC. We found that overexpression of c-Myc in Atp4b+ gastric parietal cells could induce intestinal-type gastric cancer in mice. Mechanistically, c-Myc promoted tumorigenesis via the AKT/mTOR pathway. Furthermore, AKT inhibitor (MK-2206) or mTOR inhibitor (Rapamycin) inhibited the proliferation of c-Myc overexpressing gastric cancer cell lines. Thus, our findings highlight that gastric cancer can be induced by c-Myc overexpression through activation of the AKT/mTOR pathway.
2021-08-11 | GSE145583 | GEO
Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT
The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H).
This model is described in the article:
Computational Modelling of the Metabolic States Regulated by the Kinase Akt.
Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L.
Frontiers in Systems Biology. 2012 Oct 13
Abstract:
Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism.
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2024-09-02 | BIOMD0000000426 | BioModels
Project description:Phosphoinositide-3-kinase/protein-kinaseB/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling plays an important role in breast cancer (BC). Its interaction with estrogen receptor (ER) signalling becomes more complex and inter-dependent with acquired endocrine resistance. Targeting mTOR combined with endocrine therapy has shown clinical utility, however, a negative feedback-loop exists downstream of PI3K/AKT/mTOR. Direct blockade of AKT together with endocrine therapy may improve BC treatment. AZD5363, a novel pan-AKT kinase catalytic inhibitor, was examined in a panel of ER+ BC cell lines (MCF7, HCC1428, T47D, ZR75.1) adapted to long-term-estrogen-deprivation (LTED) or tamoxifen (TamR). AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) except HCC1428 and HCC1428-LTED. T47D-LTED and ZR75-LTED were the most sensitive of the lines (GI50~100nM). AZD5363 re-sensitised TamR cells to tamoxifen and acted synergistically with fulvestrant. AZD5363 decreased p-AKT/mTOR targets leading to a reduction in ERα-mediated transcription in a context specific manner and concomitant decrease in recruitment of ER and CREB-binding protein (CBP) to estrogen-response-elements located on the TFF1, PGR and GREB1 promoters. Furthermore, AZD5363 reduced expression of cell-cycle-regulatory proteins. Global gene expression highlighted ERBB2-ERBB3, ERK5 and IGF1 signaling pathways driven by MYC as potential feedback-loops. Combined treatment with AZD5363 and fulvestrant showed synergy in an ER+ patient derived xenograft and delayed tumour progression post-cessation of therapy. These data support the combination of AZD5363 with fulvestrant as a potential therapy for BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response, supporting the need for clinical evaluation. Cell lines were treated in biological triplicates in the absence of estrogen with or without AZD5363 for 24hours in order to identify gene changes associated with perturbation of AKT signalling
2015-06-29 | E-GEOD-69893 | biostudies-arrayexpress
Project description:Although 3-Phosphoinositide-dependent protein kinase-1 (PDK1) has been predominately linked to PI3K-AKT pathway, it may also evoke additional signaling outputs to promote tumorigenesis. Here we report that PDK1 directly induces phosphorylation of Polo-like kinase 1 (PLK1), which in turn induces Myc phosphorylation and protein accumulation. We show that PDK1-PLK1-Myc signaling is critical for cancer cell growth and survival and small molecule inhibition of PDK1/PLK1 provides an effective approach for therapeutic targeting Myc-dependency. Intriguingly, PDK1-PLK1-Myc signaling induces an embryonic stem cell-like gene signature associated with aggressive tumor behaviors and is a robust signaling axis driving cancer stem cell (CSC) self renewal. Finally, we show that PLK1 inhibitor synergizes with mTOR inhibitor to induce synergistic anti-tumor effect in colorectal cancer by antagonizing a compensatory Myc induction. These findings identify a novel pathway in human cancer and CSC activation and provide a therapeutic strategy for targeting Myc-associated tumorigenesis and therapeutic resistance. Gene expression profiling of Human Embryonic Kidney Cells (HEK-TERV) under different conditions: PMN, PDK1, MYC and E545K
2013-07-31 | E-GEOD-30669 | biostudies-arrayexpress