The Role of β-Arrestins in Regulating Stem Cell Phenotypes in Normal and Tumorigenic Cells

Kallifatidis, Georgios; Mamouni, Kenza; Lokeshwar, Bal L.

doi:10.3390/ijms21239310

Cited by 8 publications

(11 citation statements)

References 82 publications

(126 reference statements)

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“…Indeed, some of the abnormal AS events were associated with drug sensitivity and resistance of NSCLC (Motegi et al, 2019;Pilié et al, 2019) as well as cell adhesion molecule binding process (Song et al, 2013;Hintermann and Christen, 2019). Our KEGG analysis showed that the genes in the m6A-related AS events significantly participated in the GPCR signaling in LUAD, and the latter is mediated by three major G protein subclasses and each subclass also has multiple proteins that are products due to the AS events (Kang et al, 2015;Kallifatidis et al, 2020). Similarly, we found the m6A-related AS events in the TGF-β signaling in LUSC.…”

Section: Discussionmentioning

confidence: 84%

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Zhao

Cai

Zhang

et al. 2021

Front. Mol. Biosci.

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Aberrant N6-methyladenosine (m6A) RNA methylation regulatory genes and related gene alternative splicing (AS) could be used to predict the prognosis of non–small cell lung carcinoma. This study focused on 13 m6A regulatory genes (METTL3, METTL14, WTAP, KIAA1429, RBM15, ZC3H13, YTHDC1, YTHDC2, YTHDF1, YTHDF2, HNRNPC, FTO, and ALKBH5) and expression profiles in TCGA-LUAD (n = 504) and TCGA-LUSC (n = 479) datasets from the Cancer Genome Atlas database. The data were downloaded and bioinformatically and statistically analyzed, including the gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. There were 43,948 mRNA splicing events in lung adenocarcinoma (LUAD) and 46,020 in lung squamous cell carcinoma (LUSC), and the data suggested that m6A regulators could regulate mRNA splicing. Differential HNRNPC and RBM15 expression was associated with overall survival (OS) of LUAD and HNRNPC and METTL3 expression with the OS of LUSC patients. Furthermore, the non–small cell lung cancer prognosis-related AS events signature was constructed and divided patients into high- vs. low-risk groups using seven and 14 AS genes in LUAD and LUSC, respectively. The LUAD risk signature was associated with gender and T, N, and TNM stages, but the LUSC risk signature was not associated with any clinical features. In addition, the risk signature and TNM stage were independent prognostic predictors in LUAD and the risk signature and T stage were independent prognostic predictors in LUSC after the multivariate Cox regression and receiver operating characteristic analyses. In conclusion, this study revealed the AS prognostic signature in the prediction of LUAD and LUSC prognosis.

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Section: Discussionmentioning

confidence: 84%

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Zhao

Cai

Zhang

et al. 2021

Front. Mol. Biosci.

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“…Among the increased proteins following RBPMS knockdown, the two ARRB members—ARRB1 and ARRB2—are deregulated in many cancer types and have been linked to the inhibition of the senescence and growth as well as the promotion of the self-renewal, progression, and invasion of cancerous cells [ 39 , 40 , 81 ]. Moreover, CPT1A plays a crucial role in radioresistant and chemoresistant phenotypes in diverse cancer types [ 41 , 42 , 82 ].…”

Section: Discussionmentioning

confidence: 99%

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

Rabelo-Fernández

Santiago-Sánchez

Sharma

et al. 2022

IJMS

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Worldwide, the number of cancer-related deaths continues to increase due to the ability of cancer cells to become chemotherapy-resistant and metastasize. For women with ovarian cancer, a staggering 70% will become resistant to the front-line therapy, cisplatin. Although many mechanisms of cisplatin resistance have been proposed, the key mechanisms of such resistance remain elusive. The RNA binding protein with multiple splicing (RBPMS) binds to nascent RNA transcripts and regulates splicing, transport, localization, and stability. Evidence indicates that RBPMS also binds to protein members of the AP-1 transcription factor complex repressing its activity. Until now, little has been known about the biological function of RBPMS in ovarian cancer. Accordingly, we interrogated available Internet databases and found that ovarian cancer patients with high RBPMS levels live longer compared to patients with low RBPMS levels. Similarly, immunohistochemical (IHC) analysis in a tissue array of ovarian cancer patient samples showed that serous ovarian cancer tissues showed weaker RBPMS staining when compared with normal ovarian tissues. We generated clustered regularly interspaced short palindromic repeats (CRISPR)-mediated RBPMS knockout vectors that were stably transfected in the high-grade serous ovarian cancer cell line, OVCAR3. The knockout of RBPMS in these cells was confirmed via bioinformatics analysis, real-time PCR, and Western blot analysis. We found that the RBPMS knockout clones grew faster and had increased invasiveness than the control CRISPR clones. RBPMS knockout also reduced the sensitivity of the OVCAR3 cells to cisplatin treatment. Moreover, β-galactosidase (β-Gal) measurements showed that RBPMS knockdown induced senescence in ovarian cancer cells. We performed RNAseq in the RBPMS knockout clones and identified several downstream-RBPMS transcripts, including non-coding RNAs (ncRNAs) and protein-coding genes associated with alteration of the tumor microenvironment as well as those with oncogenic or tumor suppressor capabilities. Moreover, proteomic studies confirmed that RBPMS regulates the expression of proteins involved in cell detoxification, RNA processing, and cytoskeleton network and cell integrity. Interrogation of the Kaplan–Meier (KM) plotter database identified multiple downstream-RBPMS effectors that could be used as prognostic and response-to-therapy biomarkers in ovarian cancer. These studies suggest that RBPMS acts as a tumor suppressor gene and that lower levels of RBPMS promote the cisplatin resistance of ovarian cancer cells.

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“…ARRB1 also enhances endothelial cell proliferation and tube formation triggered by VEGF-C [9] .ARRB1 has been demonstrated to be important in the control of stem cell characteristics, with a role in both normal and malignant stem cells [14] . ARRB stimulates the proliferation of embryonic stem cells, and in the dentate gyrus (DG) of the adult hippocampus, ARRB1 also regulates BMP2 transcription to regulate the proliferation of neural precursors.…”

Section: Discussionmentioning

confidence: 99%

ARRB1 reverses 5-FU-induced chemotherapeutic intestinal mucosal injury by protecting intestinal barrier and stem cell function

zhang

Zhao

et al. 2022

Preprint

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Chemotherapy-induced intestinal mucosal injury(CIMI)is a common side effect of chemotherapy, and its mechanism is complex. Previous studies have demonstrated that Armillariella tabescens polysaccharides (ATPS) exert intestinal mucosal protective effects by upregulating tight junction protein expression and reducing apoptosis of intestinal epithelial cells, and the expression of β-arrestin 1 (ARRB 1) is altered during this process. The aim of this study was to investigate the role of ARRB 1 in ATPS protection against chemotherapeutic intestinal mucosal injury induced by 5-fluorouracil (5-FU). A CIMI model was established by intraperitoneal injection of 5-FU (50 mg/kg), and ATPS (200 mg/kg) was administered by gavage once a day for treatment. Body weight changes of mice were monitored. The gross appearance of intestinal tissues was observed, and hematoxylin and eosin staining was performed for histological analysis and histological activity score. Immunohistochemistry was performed to detect the expression of tight junction ( TJ ) protein markers. Organoid cultures were performed to detect the status of intestinal stem cells. The results showed that ATPS ameliorated 5-FU-induced intestinal inflammation in WT mice by increasing body weight, reducing histopathological damage, and increasing intestinal tight junction protein expression, and organoid formation rate. However, the alleviating effect of ATPS on CIMI was not significant in ARRB1-KO mice. Therefore, we suggest that ARRB1 is involved in the repair of CIMI damage by ATPS, and the mechanism may be related to the regulation of small intestinal tissue TJ protein production by ARRB1 to protect intestinal stem cells from chemotherapeutic damage.

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The Role of β-Arrestins in Regulating Stem Cell Phenotypes in Normal and Tumorigenic Cells

Cited by 8 publications

References 82 publications

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

N6-Methyladenosine RNA Methylation Regulator-Related Alternative Splicing (AS) Gene Signature Predicts Non–Small Cell Lung Cancer Prognosis

Reduced RBPMS Levels Promote Cell Proliferation and Decrease Cisplatin Sensitivity in Ovarian Cancer Cells

ARRB1 reverses 5-FU-induced chemotherapeutic intestinal mucosal injury by protecting intestinal barrier and stem cell function

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