Targeting endothelin 1 receptor-miR-200b/c-ZEB1 circuitry blunts metastatic progression in ovarian cancer

Sestito, Rosanna; Cianfrocca, Roberta; Tocci, Piera; Rosanò, Laura; Sacconi, Andrea; Blandino, Giovanni; Bagnato, Anna

doi:10.1038/s42003-020-01404-3

Cited by 16 publications

(19 citation statements)

References 64 publications

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“…In particular, the interplay between miRNAs and transcriptional regulators has been shown to regulate key developmental events or cell-fate decisions [41][42][43]. In particular, one well-described network motif, the double-negative feedback loop, is thought to regulate many binary cell-fate decisions [42][43][44]. This regulatory mechanism implies that one miRNA targets a transcriptional regulator, which in turn controls the expression of this miRNA and usually acts as a switch between two alternative cell states [42][43][44][45].…”

Section: Discussionmentioning

confidence: 99%

“…In particular, one well-described network motif, the double-negative feedback loop, is thought to regulate many binary cell-fate decisions [42][43][44]. This regulatory mechanism implies that one miRNA targets a transcriptional regulator, which in turn controls the expression of this miRNA and usually acts as a switch between two alternative cell states [42][43][44][45]. In this study, we propose that, in ccRCC, miR-21 and PPAR-α function in a double-negative feedback loop, where miR-21 and PPAR-α mutually repress each other to control lipid metabolism (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

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A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Goujon

Woszczyk

Gaudelot

et al. 2022

Cancers

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Clear cell renal cell carcinoma (ccRCC) is the main histotype of kidney cancer, which is typically highly resistant to conventional therapies and known for abnormal lipid accumulation. In this context, we focused our attention on miR-21, an oncogenic miRNA overexpressed in ccRCC, and peroxysome proliferator-activated receptor-α (PPAR- α), one master regulator of lipid metabolism targeted by miR-21. First, in a cohort of 52 primary ccRCC samples, using RT-qPCR and immunohistochemistry, we showed that miR-21 overexpression was correlated with PPAR-α downregulation. Then, in ACHN and 786-O cells, using RT-qPCR, the luciferase reporter gene, chromatin immunoprecipitation, and Western blotting, we showed that PPAR-α overexpression (i) decreased miR-21 expression, AP-1 and NF-κB transcriptional activity, and the binding of AP-1 and NF-κB to the miR-21 promoter and (ii) increased PTEN and PDCD4 expressions. In contrast, using pre-miR-21 transfection, miR-21 overexpression decreased PPAR-α expression and transcriptional activity mediated by PPAR-α, whereas the anti-miR-21 (LNA-21) strategy increased PPAR-α expression, but also the expression of its targets involved in fatty acid oxidation. In this study, we showed a double-negative feedback interaction between miR-21 and PPAR-α. In ccRCC, miR-21 silencing could be therapeutically exploited to restore PPAR-α expression and consequently inhibit the oncogenic events mediated by the aberrant lipid metabolism of ccRCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Goujon

Woszczyk

Gaudelot

et al. 2022

Cancers

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“…Consistently, previous studies reported that a bypass of the regular PTPN6 polyadenylation signal allows the transcription of the downstream miR-200c [ 42 ]. miR-200c was known to be involved in the metastasis and invasion of ovarian carcinoma due to its functional regulation of epithelial-to-mesenchymal transition (EMT) [ 43 , 44 ]. Its co-transcription with PTPN6 provides a potential way to target miR-200c in ovarian cancer.…”

Section: Resultsmentioning

confidence: 99%

Pan-Cancer Analysis Reveals Common and Specific Relationships between Intragenic miRNAs and Their Host Genes

2021

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MicroRNAs (miRNAs) are small endogenous non-coding RNAs that play important roles in regulating gene expression. Most miRNAs are located within or close to genes (host). miRNAs and their host genes have either coordinated or independent transcription. We performed a comprehensive investigation on co-transcriptional patterns of miRNAs and host genes based on 4707 patients across 21 cancer types. We found that only 11.6% of miRNA-host pairs were co-transcribed consistently and strongly across cancer types. Most miRNA-host pairs showed a strong coexpression only in some specific cancer types, demonstrating a high heterogenous pattern. For two particular types of intergenic miRNAs, readthrough and divergent miRNAs, readthrough miRNAs showed higher coexpression with their host genes than divergent ones. miRNAs located within non-coding genes had tighter co-transcription with their hosts than those located within protein-coding genes, especially exonic and junction miRNAs. A few precursor miRNAs changed their dominate form between 5′ and 3′ strands in different cancer types, including miR-486, miR-99b, let-7e, miR-125a, let-7g, miR-339, miR-26a, miR-16, and miR-218, whereas only two miRNAs with multiple host genes switched their co-transcriptional partner in different cancer types (miR-219a-1 with SLC39A7/HSD17B8 and miR-3615 with RAB37/SLC9A3R1). miRNAs generated from distinct precursors (such as miR-125b from miR-125b-1 or miR-125b-2) were more likely to have cancer-dependent main contributors. miRNAs and hosts were less co-expressed in KIRC than other cancer types, possibly due to its frequent VHL mutations. Our findings shed new light on miRNA biogenesis and cancer diagnosis and treatments.

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“…Multiple extra-cellular signals can initiate an EMT-related gene expression program through significant cross-talk between co-factors and transcription factors (TF) forming regulatory networks controlling the metastatic cascade [ 5 , 6 ]. In this regard, it has been widely demonstrated that endothelin-1 (ET-1) axis, including the peptide ligand ET-1 and the two G-protein coupled receptors (GPGR; ET A R and ET B R), is a potent inducer of EMT by regulating the EMT-TF, such as Snail and zinc finger E-box binding homeobox 1 (ZEB1), that repress epithelial genes and stimulate the expression of mesenchymal components [ 7 – 10 ]. ZEB1 is a prime element of a network of TF controlling EMT by directly repressing E-cadherin [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…It has been widely demonstrated that ZEB1 can participate in double-negative feedback loops with microRNA (miR)-200 family members, strong inducers of epithelial differentiation [ 11 – 13 ]. Recent evidence in OC has pointed out the role of ET-1/ET A R axis in regulating the ZEB1/miR-200 circuitry [ 10 ]. In particular, our results indicate that ET A R activation by ET-1 promotes OC progression by inducing ZEB1 expression and suppressing miR-200.…”

Section: Introductionmentioning

confidence: 99%

Functional interaction between endothelin-1 and ZEB1/YAP signaling regulates cellular plasticity and metastasis in high-grade serous ovarian cancer

Sestito

Tocci

Roman

et al. 2022

J Exp Clin Cancer Res

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Background Epithelial-to-mesenchymal transition (EMT) encompasses a highly dynamic and complex key process which leads to metastatic progression. In high-grade serous ovarian carcinoma (HG-SOC), endothelin-1 (ET-1)/endothelin A receptor (ETAR) signaling promotes EMT driving tumor progression. However, the complex nature of intertwined regulatory circuits activated by ET-1 to trigger the metastatic process is not fully elucidated. Methods The capacity of ET-1 pathway to guide a critical transcriptional network that is instrumental for metastatic growth was identified in patient-derived HG-SOC cells and cell lines through immunoblotting, q-RT-PCR, co-immunoprecipitation, in situ proximity ligation, luciferase reporter, chromatin immunoprecipitation assays and publicly available databases. Functional assays in HG-SOC cells and HG-SOC xenografts served to test the inhibitory effects of ET-1 receptors (ET-1R) antagonist in vitro and in vivo. Results We demonstrated that ET-1/ETAR axis promoted the direct physical ZEB1/YAP interaction by inducing their nuclear accumulation in HG-SOC cells. Moreover, ET-1 directed their engagement in a functional transcriptional complex with the potent oncogenic AP-1 factor JUN. This led to the aberrant activation of common target genes, including EDN1 (ET-1) gene, thereby creating a feed-forward loop that sustained a persistent ET-1/ZEB1 signaling activity. Notably, ET-1-induced Integrin-linked kinase (ILK) signaling mediated the activation of YAP/ZEB1 circuit driving cellular plasticity, invasion and EMT. Of therapeutic interest, treatment of HG-SOC cells with the FDA approved ET-1R antagonist macitentan, targeting YAP and ZEB1-driven signaling, suppressed metastasis in vivo in mice. High gene expression of ETAR/ILK/YAP/AP-1/ZEB1 was a strong predictor of poor clinical outcome in serous ovarian cancer patients, indicating the translational relevance of this signature expression. Conclusions This study provides novel mechanistic insights of the ET-1R-driven mediators that support the ability of HG-SOC to acquire metastatic traits which include the cooperation of YAP and ZEB1 regulatory circuit paving the way for innovative treatment of metastatic ovarian cancer.

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Targeting endothelin 1 receptor-miR-200b/c-ZEB1 circuitry blunts metastatic progression in ovarian cancer

Cited by 16 publications

References 64 publications

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

A Double-Negative Feedback Interaction between miR-21 and PPAR-α in Clear Renal Cell Carcinoma

Pan-Cancer Analysis Reveals Common and Specific Relationships between Intragenic miRNAs and Their Host Genes

Functional interaction between endothelin-1 and ZEB1/YAP signaling regulates cellular plasticity and metastasis in high-grade serous ovarian cancer

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