Functional relationship between CFTR and RAC3 expression for maintaining cancer cell stemness in human colorectal cancer

Palma, Alejandra Graciela; Machado, Mileni Soares; Lira, María Cecilia; Rosa, Francisco; Rubio, Miguel; Marino, Gabriela Inés; Kotsias, Basilio A.; Costas, Mónica Alejandra

doi:10.1007/s13402-021-00589-x

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…RAC3 is a member of the SRC/p160 coactivator family that also includes SRC-1 (NCoA1) and SRC-2 (GRIP1, TIF2, and NCoA2) [ 34 ]. RAC3 expression is frequently elevated in a diverse range of human cancers, including colon carcinoma, lung adenocarcinoma, breast cancer, pancreatic cancer, and bladder cancer, which has been verified to be a crucial regulator in tumor initiation [ 35 ]. For example, RAC3 promotes the growth of breast cancer cells through the p21-activated kinase-dependent pathway [ 36 ], enhances the proliferation of cancer cells in vitro and in vivo, and facilitates proliferation, migration, and invasion of bladder cancer cells through the PYCR1/JAK/STAT axis [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

Chen,

Hu,

Xiong

et al. 2024

Cell Death Dis

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Ewing’s sarcoma (ES) represents a rare yet exceedingly aggressive neoplasm that poses a significant health risk to the pediatric and adolescent population. The clinical outcomes for individuals with relapsed or refractory ES are notably adverse, primarily attributed to the constrained therapeutic alternatives available. Despite significant advancements in the field, molecular pathology-driven therapeutic strategies have yet to achieve a definitive reduction in the mortality rates associated with ES. Consequently, there exists an imperative need to discover innovative therapeutic targets to effectively combat ES. To reveal the mechanism of the SETD8 (also known as lysine methyltransferase 5A) inhibitor UNC0379, cell death manners were analyzed with different inhibitors. The contributions of SETD8 to the processes of apoptosis and ferroptosis in ES cells were evaluated employing the histone methyltransferase inhibitor UNC0379 in conjunction with RNA interference techniques. The molecular regulatory mechanisms of SETD8 in ES were examined through the application of RNA sequencing (RNA-seq) and mass spectrometry-based proteomic analysis. Moreover, nude mouse xenograft models were established to explore the role of SETD8 in ES in vivo. SETD8, a sole nucleosome-specific methyltransferase that catalyzes mono-methylation of histone H4 at lysine 20 (H4K20me1), was found to be upregulated in ES, and its overexpression was associated with dismal outcomes of patients. SETD8 knockdown dramatically induced the apoptosis and ferroptosis of ES cells in vitro and suppressed tumorigenesis in vivo. Mechanistic investigations revealed that SETD8 facilitated the nuclear translocation of YBX1 through post-transcriptional regulatory mechanisms, which subsequently culminated in the transcriptional upregulation of RAC3. In summary, SETD8 inhibits the apoptosis and ferroptosis of ES cells through the YBX1/RAC3 axis, which provides new insights into the mechanism of tumorigenesis of ES. SETD8 may be a potential target for clinical intervention in ES patients.

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Section: Discussionmentioning

confidence: 99%

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

Chen,

Hu,

Xiong

et al. 2024

Cell Death Dis

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“…To develop the optimal prognosis signature, we implemented univariate Cox proportional hazards regression analysis (uni-Cox), the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, and multivariate Cox regression analysis (multi-Cox) with “survival” [ 11 ] and “glmnet” [ 12 ] R package. The regression coefficients obtained from multi-Cox were used to determine the Gemcitabine-based Immune-related Risk Score (GIRS) for each patient via the “survival” R package [ 11 ]. Specifically, the GIRS formula was calculated as follows: where Expr (i) represents the expression level of the gene in patient i, and Coefficient (i) is the multi-Cox coefficient corresponding to gene i.…”

Section: Methodsmentioning

confidence: 99%

“…To verify the accuracy of the GIRS, the Kaplan–Meier (K–M) survival analysis was conducted using the “survival” [ 11 ] and “survminer” [ 13 ] R package. The ROC curves (1-,3-,5-year) were generated with the “timeROC” R package [ 14 ] and C-index was determined by the R package “survcomp” [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

“…where Expr (i) represents the expression level of the gene in patient i, and Coefficient (i) is the multi-Cox coefficient corresponding to gene i. To be more specific, GIRS was calculated as follows: expression of OAS1 To verify the accuracy of the GIRS, the Kaplan-Meier (K-M) survival analysis was conducted using the "survival" [11] and "survminer" [13] R package. The ROC curves (1-,3-,5-year) were generated with the "timeROC" R package [14] and C-index was determined by the R package "survcomp" [15].…”

Section: Establishment and Validation Of Gemcitabine-based Immune-rel...mentioning

confidence: 99%

“…Previous studies have shown that RAC3, a small GTPbinding protein belonging to the RAS superfamily, controls a variety of biological processes such as cell growth, cytoskeletal reorganization, and protein kinase activation [8]. Importantly, it served as an oncogene in a variety of tumors, including BCa, which was indicated closely associated with cancer invasion [9][10][11]. Cheng et al [9] found that RAC3 expression was overexpressed in BCa tissues and cells, and patients with up-regulated RAC3 had worse survival outcomes.…”

Section: Pik-75 Down-regulated the Gene Expression Of Rac3 At Mrna An...mentioning

confidence: 99%

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Deciphering the prognostic features of bladder cancer through gemcitabine resistance and immune-related gene analysis and identifying potential small molecular drug PIK-75

Cai,

Feng,

et al. 2024

Cancer Cell Int

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Background Bladder cancer (BCa) stands out as a prevalent and highly lethal malignancy worldwide. Chemoresistance significantly contributes to cancer recurrence and progression. Traditional Tumor Node Metastasis (TNM) stage and molecular subtypes often fail to promptly identify treatment preferences based on sensitivity. Methods In this study, we developed a prognostic signature for BCa with uni-Cox + LASSO + multi-Cox survival analysis in multiple independent cohorts. Six machine learning algorithms were adopted to screen out the hub gene, RAC3. IHC staining was used to validate the expression of RAC3 in BCa tumor tissue. RT-qPCR and Western blot were performed to detect and quantify the mRNA and protein levels of RAC3. CCK8, colony formation, wound healing, and flow cytometry analysis of apoptosis were employed to determine cell proliferation, migration, and apoptosis. Molecular docking was used to find small target drugs, PIK-75. 3D cell viability assay was applied to evaluate the ATP viability of bladder cancer organoids before and after PIK-75 treated. Results The established clinical prognostic model, GIRS, comprises 13 genes associated with gemcitabine resistance and immunology. This model has demonstrated robust predictive capabilities for survival outcomes across various independent public cohorts. Additionally, the GIRS signature shows significant correlations with responses to both immunotherapy and chemotherapy. Leveraging machine learning algorithms, the hub gene, RAC3, was identified, and potential upstream transcription factors were screened through database analysis. IHC results showed that RAC3 was higher expressed in GEM-resistant BCa patients. Employing molecular docking, the small molecule drug PIK-75, as binding to RAC3, was identified. Experiments on cell lines, organoids and animals validated the biological effects of PIK-75 in bladder cancer. Conclusions The GIRS signature offers a valuable complement to the conventional anatomic TNM staging system and molecular subtype stratification in bladder cancer. The hub gene, RAC3, plays a crucial role in BCa and is significantly associated with resistance to gemcitabine. The small molecular drug, PIK-75 having the potential as a therapeutic agent in the context of gemcitabine-resistant and immune-related pathways.

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Hypomethylated gene RAC3 induces cell proliferation and invasion by increasing FASN expression in endometrial cancer

Meijuan

Liu²,

Fang

et al. 2022

The International Journal of Biochemistry & Cell Biology

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Functional relationship between CFTR and RAC3 expression for maintaining cancer cell stemness in human colorectal cancer

Cited by 5 publications

References 40 publications

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

SETD8 inhibits apoptosis and ferroptosis of Ewing’s sarcoma through YBX1/RAC3 axis

Deciphering the prognostic features of bladder cancer through gemcitabine resistance and immune-related gene analysis and identifying potential small molecular drug PIK-75

Hypomethylated gene RAC3 induces cell proliferation and invasion by increasing FASN expression in endometrial cancer

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