ARRB1-Promoted NOTCH1 Degradation Is Suppressed by OncomiR miR-223 in T-cell Acute Lymphoblastic Leukemia

Shu, Yi; Wang, Yi; Lv, Wen-Qiong; Peng, Dan-Yi; Li, Juan; Zhang, Hang; Jiang, Guangjie; Yang, Bi-Jie; Liu, Shan; Zhang, Jia; Chen, Yanhua; Tang, Shi; Wan, Ke-Xing; Yuan, Jun-Tao; Guo, Wei; Fu, Guo; Qi, Xin-Kun; Liu, Zhi-Dai; Liu, Haiyan; Yang, Chao; Zhang, Linghuan; Liu, Fang-jie; Yu, Jie; Zhang, Penghui; Qu, Bin; Zhao, Hui; He, Tong‐Chuan; Zou, Lin

doi:10.1158/0008-5472.can-19-1471

Cited by 23 publications

(21 citation statements)

References 46 publications

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“…This study did not investigate the activation state of Notch signaling or the cellular levels of NICD and downstream targets like HES1 during a physiological repair response or in disease. Of note, the meta-analysis of the published transcriptomics datasets highlighted poten-tial dysregulation of upstream regulators able to activate (MECOM and USP9X) [50,51] or inhibit Notch (e.g., ARRB1) [52]. In addition, this meta-analysis indicated additional complexity in Notch regulation through potential alteration of Notch co-activators (KAT2A, CREBBP, EP300) and co-repressors (HDACs) that modulate its downstream target gene transcription and cellular functions [23].…”

Section: Discussionmentioning

confidence: 88%

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

Iosifidis

Sutanto

Montgomery

et al. 2021

JPM

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The airway epithelium of children with wheeze is characterized by defective repair that contributes to disease pathobiology. Dysregulation of developmental processes controlled by Notch has been identified in chronic asthma. However, its role in airway epithelial cells of young children with wheeze, particularly during repair, is yet to be determined. We hypothesized that Notch is dysregulated in primary airway epithelial cells (pAEC) of children with wheeze contributing to defective repair. This study investigated transcriptional and protein expression and function of Notch in pAEC isolated from children with and without wheeze. Primary AEC of children with and without wheeze were found to express all known Notch receptors and ligands, although pAEC from children with wheeze expressed significantly lower NOTCH2 (10-fold, p = 0.004) and higher JAG1 (3.5-fold, p = 0.002) mRNA levels. These dysregulations were maintained in vitro and cultures from children with wheeze displayed altered kinetics of both NOTCH2 and JAG1 expression during repair. Following Notch signaling inhibition, pAEC from children without wheeze failed to repair (wound closure rate of 76.9 ± 3.2%). Overexpression of NOTCH2 in pAEC from children with wheeze failed to rescue epithelial repair following wounding. This study illustrates the involvement of the Notch pathway in airway epithelial wound repair in health and disease, where its dysregulation may contribute to asthma development.

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Section: Discussionmentioning

confidence: 88%

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

Iosifidis

Sutanto

Montgomery

et al. 2021

JPM

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“…Conversely, when ARRB1 is exogenously expressed, T‐ALL proliferation is impaired and survival of T‐ALL xenograft animals improved. Together, these data show how miR‐223‐3p impairs the tumor suppressive role of ARRB1 in T‐ALL, thus upregulating Notch and creating a positive feedback loop that fosters T‐ALL progression (Shu et al, 2020 ). miR‐223 is also involved in another important pathway which is commonly dysregulated in T‐ALL, the TAL1/FBXW7 axis.…”

Section: Mir ‐223 In Cancer Onset and Progressionmentioning

confidence: 90%

“…In T‐cell acute lymphoblastic leukemia (T‐ALL), a very aggressive cancer of the bone marrow, the expression of miR‐223 is increased compared with their normal counterpart, due to the action of the Notch pathway, which is subjected to activating mutations in most T‐ALL cases, and the NF‐κB pathway (Chiaretti et al, 2010 ; Mavrakis et al, 2011 ; Shu et al, 2020 ). In vitro experiments demonstrate that miR‐223‐3p targets the 3′‐UTR of ARRB1, a member of the β‐arrestin family which facilitates Notch1 ubiquitination and degradation.…”

Section: Mir ‐223 In Cancer Onset and Progressionmentioning

confidence: 99%

The many facets of miR‐223 in cancer: Oncosuppressor, oncogenic driver, therapeutic target, and biomarker of response

et al. 2021

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Given their intrinsic pleiotropism, microRNAs (miR) play complex biological roles, in both normal and pathological conditions. Often the same miR can act as oncogene or oncosuppressor, depending on the biological process dysregulated in each specific tissue. miR-223 does not represent an exception to this rule and its functions greatly differ in different contexts. miR-223 has been widely studied in the hematopoietic compartment, where it plays a central role in innate immune response, regulating myeloid differentiation and granulocytes function. Accordingly, dysregulated expression of miR-223 has been associated to different inflammatory disorders and tumors arising from the immune compartment. Most carcinomas, breast cancer being the most studied, display loss of miR-223. However, in gastro-esophageal cancers miR-223 is frequently overexpressed and correlates with worse prognosis. A link between miR-223 and response to CDK4/6-inhibitors has been recently proposed, suggesting a role as biomarker of therapeutic response. The notion that one of the most commonly mutated protein in cancer, mutant p53, binds the promoter of miR-223 and suppresses its transcription, adds a further level of complexity to the full understanding of miR-223 in cancer. In this review, we will summarize the current knowledge on the molecular networks that alter or are altered by miR-223, in different cancer types. We will discuss if the times are ready for the exploitation of miR-223 as predictive biomarker of treatment response or, even, as therapeutic target, in specific settings. Finally, we will suggest which could be the next steps to be taken for a realistic clinical application of miR-223.

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“…Our western bolt results confirmed that whether it is synovial tissue or FLS, the expression of TGCT Arrb2 was higher than that of OA. However, some studies have shown that the expression of Arrb1 is also essential for maintaining the malignant phenotype of tumors (33)(34)(35). Therefore, we also tested the expression of Arrb1 and found that there was no difference between TGCT and OA.…”

Section: (C) Heatmap Of the Differentially Expressed Mrna Patterns In Tgct Versus Oa Synovitis The Relative Expression Is Indicated By Comentioning

confidence: 92%

β-Arrestin2 Inhibits the Apoptosis and Facilitates the Proliferation of Fibroblast-like Synoviocytes in Diffuse-type Tenosynovial Giant Cell Tumor

Cao

Zhang

Cheng

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm of uncertain etiology, and the efficacy of surgical resection is not satisfactory. Therefore, there is an urgent need to explore the pathogenesis and identify novel therapeutic targets for TGCT. Materials and Methods: Synovial tissues were collected from patients with TGCT and osteoarthritis (OA). Differences of mRNA expression between TGCT and OA were explored using mRNA-seq. In addition, fibroblast-like synoviocytes (FLS) were treated with small interfering RNA (siRNA) or adenovirus in order to knockdown or overexpress β-arrestin2 (Arrb2), respectively. FLS proliferation and apoptosis were evaluated using the MTT assay and the caspase 3 activity assay, respectively. Results: The expression of Arrb2 in TGCT was significantly higher than that in OA. The overexpression of Arrb2 promoted the proliferation of FLS and inhibited its apoptosis, while knocking down Arrb2 had the opposite effect. Further studies showed that Arrb2 can activate the PI3K-Akt signaling pathway, leading to increased proliferation of TGCT. Conclusion: Arrb2 facilitates the proliferation and inhibits the apoptosis of TGCT FLS through activating the PI3K-Akt cell survival pathway, providing new insight into the molecular mechanism of TGCT.Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm characterized by villous and nodular lesions of an uncertain etiology (1). The main clinical features of TGCT are synovial hyperplasia and recurrence. The hyperplastic synovial tissue will produce a large amount of bloody synovial fluid and cause excessive swelling of the joints, further causing joint pain and dysfunction (2). Uncontrollable excessive synovial proliferation can even cause malignant transformation of TGCT and result in amputation (3). Fibroblast-like synoviocytes (FLS), as the main constituent cell type of TGCT, play an important role in its proliferation, recurrence, and malignant transformation (4). Because its pathogenesis is currently unclear, the therapeutic mainstay of TGCT is limited to removing the entire pathological synovial tissue (5). However, surgical resection alone often cannot completely remove the diseased synovium; the residual synovium will rapidly proliferate and cause postoperative recurrence, at a rate of approximately 21-50% (6). Postoperative radiotherapy is often needed to reduce recurrence, but radiotherapy can lead to a series of complications such as joint adhesion (7). Therefore, there is an urgent need to explore the pathogenesis of TGCT and identify novel therapeutic targets, especially focusing on the inhibition of its proliferation and recurrence.β-Arrestin 2 (Arrb2) is widely expressed in various tissues and involved in mediating G protein coupled receptor (GPCR) desensitization, internalization, degradation and 461 This article is freely accessible online.

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ARRB1-Promoted NOTCH1 Degradation Is Suppressed by OncomiR miR-223 in T-cell Acute Lymphoblastic Leukemia

Cited by 23 publications

References 46 publications

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

Dysregulated Notch Signaling in the Airway Epithelium of Children with Wheeze

The many facets of miR‐223 in cancer: Oncosuppressor, oncogenic driver, therapeutic target, and biomarker of response

β-Arrestin2 Inhibits the Apoptosis and Facilitates the Proliferation of Fibroblast-like Synoviocytes in Diffuse-type Tenosynovial Giant Cell Tumor

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