RNA-binding protein CUGBP1 controls the differential INSR splicing in molecular subtypes of breast cancer cells and affects cell aggressiveness

Huang, Gena; Song, Chen; Wang, Ning; Qin, Tao; Sui, Silei; Obr, Alison E.; Zeng, Li; Wood, Teresa L.; LeRoith, Derek; Li, Man; Wu, Yingjie

doi:10.1093/carcin/bgz141

Cited by 17 publications

(18 citation statements)

References 38 publications

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“…differential INSR splicing in molecular subtypes of BC cells and affects cell aggressiveness [12]. And RNAbinding protein RBM38 increases PTEN expression via enhancing its mRNA stability in BC [13].Those studies along with ours indicate that lncRNAs are critical regulators for trastuzumab resistanceby binding with RBPs.…”

supporting

confidence: 67%

Exosomal Long Noncoding Rna AGAP2-AS1 Regulates Trastuzumab Resistance via Inducing Autophagy in Breast Cancer

Qian

Zhang

et al. 2020

Preprint

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Background: Trastuzumab has been widely used for treatment of HER-2-positive breast cancer patients, however, the clinical response has been restricted due to emergence of resistance. Recent studies indicate that long noncoding RNA AGAP2-AS1 (lncRNA AGAP2-AS1) plays an important role in cancer resistance. However, the precise regulatory function and therapeutic potential of AGAP2-AS1 in trastuzumab resistance is still not defined. Methods: Trastuzumab resistant cells were established. RNA sequencing and qRT-PCR were performed to identify the target gene of AGAP2-AS1. Mass spectrometry, RNA pulldown and RNA immunoprecipitation assays were performed to verify the direct interactions among AGAP2-AS1 and other associated targets, such as embryonic lethal abnormal version like RNA binding protein 1 (ELAVL1) and autophagy related 10 (ATG10). In vitro and in vivo experimental assays were done to clarify the functional role of exosomal AGAP2-AS1 in trastuzumab resistance.Results: AGAP2-AS1 promotes and disseminates trastuzumab resistance via packaging into exosomes. Exosomal AGAP2-AS1 induces trastuzumab resistance via modulating ATG10 expression and autophagy activity. Mechanically, AGAP2-AS1 is associated with ELAVL1 protein. The AGAP2-AS1-ELAVL1 complex could directly bind to the promoter region of ATG10, inducing H3K27ac and H3K4me3 enrichment, which finally activates ATG10 transcription. AGAP2-AS1-targeting antisenseoligonucleotides (ASO) substantially increased trastuzumab-induced cytotoxicity. Clinically, increased expression of serum exosomal AGAP2-AS1 was associate with poor response to trastuzumab treatment.Conclusion: ExosomalAGAP2-AS1 increased trastuzumab resistance via promoting ATG10 expression and inducing autophagy. Therefore, AGAP2-AS1 may serve aspredictive biomarker and therapeutic target for HER-2+ breast cancer patients.

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supporting

confidence: 67%

Exosomal Long Noncoding Rna AGAP2-AS1 Regulates Trastuzumab Resistance via Inducing Autophagy in Breast Cancer

Qian

Zhang

et al. 2020

Preprint

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“…Our data outlines a novel approach where we can use a SSO compound to reverse splicing in RMS cell lines. In addition to this our data potentially links the RNA binding protein CUG-BP with insulin receptor and this interplay between the two could further be exploited in therapeutic and mechanistic directions and a recent paper documented this interaction in breast cancer cells 13 .…”

Section: Resultsmentioning

confidence: 76%

“…Though only a small change in the protein composition, deletion of these 12 amino acids results in a receptor that has increased binding affinity for the IGF-2 growth factor and is capable of responding to autocrine and paracrine signaling (Figure 1A). The expression of these isoforms is regulated during development and is altered in some breast and liver cancers 4,5,13 . RMS is characterized by high levels of IGF-2, produced in an autocrine manner 9 .…”

Section: Resultsmentioning

confidence: 99%

Splice-switching of the insulin receptor in rhabdomyosarcoma: Rescuing theIR-Bisoform for better treatment options

Khurshid

Montes

Comiskey

et al. 2020

Preprint

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Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with poor prognosis for metastasis and recurrent disease. Large scale sequencing endeavors demonstrate that RMS tumors have limited mutations and a dearth of driver mutations that are precisely targetable. However, IGF2 signaling is known to be grossly altered in RMS. The IGF2 signalling molecule binds both its innate IGF1 receptor as well as the insulin-receptor-variant-A (IR-A) with high affinity. Mitogenic and proliferative signalling via the canonical IGF2 pathway is therefore augmented by IR-A. The insulin receptor (IR) which is a transmembrane tyrosine-kinase receptor exists in two alternatively spliced isoforms, IR-A and IR-B. In this study, we show that RMS patients express increased IR-A compared to control tissues that express predominantly the IR-B isoform. We also found that Hif1a is significantly increased in RMS tumors, portraying their hypoxic phenotype. Furthermore, the alternative-splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a hypoxia-responsive-element, which is also the binding site for the RNA-binding protein CUG-BP1. We designed Splice-Switching-Oligonucleotides (SSO) against this binding site to decrease the levels of IR-A in RMS cell-lines and consequently rescue the IR-B expression levels. SSO treatment resulted in significant reductions in proliferation, migration and angiogenesis. Our data show promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. Our data reveal that RMS tumors use IR alternative-splicing as yet another survival strategy which can be exploited as therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.

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“…For instance, loss of the splicing factor SRSF3 promotes hepatic carcinogenesis by favoring INSR exon 11 skipping thereby inducing IR-A expression [84]. As recently demonstrated, the RNA-binding protein CUGBP1 alters the IR-A:IR-B ratio inducing IR-A prevalence and its mitogenic effects in breast cancer cells [85]. In addition, prevalence of an IR-A/IGF2 loop drives acquired resistance to anti-IGF1R therapies [86].…”

Section: The Igf System In Cancer: a Complex Network Of Interactionsmentioning

confidence: 97%

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

Mancarella

Morrione

Scotlandi

2021

Cells

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Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.

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RNA-binding protein CUGBP1 controls the differential INSR splicing in molecular subtypes of breast cancer cells and affects cell aggressiveness

Cited by 17 publications

References 38 publications

Exosomal Long Noncoding Rna AGAP2-AS1 Regulates Trastuzumab Resistance via Inducing Autophagy in Breast Cancer

Exosomal Long Noncoding Rna AGAP2-AS1 Regulates Trastuzumab Resistance via Inducing Autophagy in Breast Cancer

Splice-switching of the insulin receptor in rhabdomyosarcoma: Rescuing theIR-Bisoform for better treatment options

Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options

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