A
            <scp>HIF</scp>
            –
            <scp>LIMD</scp>
            1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

Foxler, Daniel E.; Bridge, Katherine S.; Foster, John G.; Grevitt, Paul; Curry, Sean; Shah, Kunal M.; Davidson, Kathryn; Nagano, A.; Gadaleta, Emanuela; Rhys, Hefin; Kennedy, Paul; Hermida, Miguel A.; Chang, Ting‐Yu; Shaw, Peter E.; Reynolds, Louise E.; McKay, Tristan R.; Wang, Hsei Wei; Ribeiro, Paulo S.; Plevin, Michael J.; Lagos, Dimitrios; Lemoine, Nick R.; Rajan, Prabhakar; Graham, Trevor A.; Chelala, Claude; Hodivala‐Dilke, Kairbaan; Spendlove, Ian; Sharp, Tyson V.

doi:10.15252/emmm.201708304

Cited by 18 publications

(27 citation statements)

References 73 publications

(107 reference statements)

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“…A large number of previous studies have suggested that LIMD1 functions as a tumor suppressor (24)(25)(26)(27). In terms of molecular mechanism, LIMD1 could participate in cellular processes and pathways through its scaffold function, meaning that the tumorsuppressive function of LIMD1 is likely to be regulated by different signal cascades (28). For example, LIMD1 can regulate Hippo-YAP signaling activity (29), and its phosphorylation is necessary for mitotic progression (23).…”

Section: Discussionmentioning

confidence: 99%

miR-550a-5p Functions as a Tumor Promoter by Targeting LIMD1 in Lung Adenocarcinoma

Guo

et al. 2020

Front. Oncol.

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Lung adenocarcinoma accounts for half of all lung cancer cases in most countries. Mounting evidence has demonstrated that microRNAs play important roles in cancer progression, and some of them can be identified as potential biomarkers. This study aimed to explore the role of miR-550a-5p, a lung adenocarcinoma-associated mature microRNA screened out from the TCGA database via R-studio and Perl, with abundant expression in samples and with 5-year survival prognosis difference, as well as having not been studied in lung cancer yet. Potential target genes were predicted by the online database. Gene ontology enrichment, pathway enrichment, protein-protein interaction network, and hub genes-microRNA network were constructed by FunRich, STRING database, and Cytoscape. Then, LIMD1, a known tumor suppressor gene reported by multiple articles, was found to have a negative correlation with miR-550a-5p. The expression of miR-550a-5p was up-regulated in tumor samples and tumor-associated cell lines. Its high expression was also correlated with tumor size. Cell line A549 treated with miR-550a-5p overexpression promoted tumor proliferation, while H1299 treated with miR-550a-5p knockdown showed the opposite result. Mechanically, miR-550a-5p negatively regulated LIMD1 by directly binding to its 3 ′-UTR validated by dual luciferase assay. In summary, a new potential prognostic and therapeutic biomarker, miR-550a-5p, has been identified by bioinformatics analysis and experimental validation in vitro and in vivo, which promotes lung adenocarcinoma by silencing a known suppressor oncogene LIMD1.

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Section: Discussionmentioning

confidence: 99%

miR-550a-5p Functions as a Tumor Promoter by Targeting LIMD1 in Lung Adenocarcinoma

Guo

et al. 2020

Front. Oncol.

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“…Sharp et al confirmed that in cell and animal experiments, LIMD1 overexpression in tumor cells can inhibit the growth of tumor cells; thus, LIMD1 is regarded as a tumor suppressor gene (16,18). Sharp et al also found that as a target gene of HIF-1, LIMD1 participates in the degradation of HIF-α under hypoxic conditions through a negative feedback loop, thereby exerting the anticancer effect (19). In addition, LIMD1 interacts with the Rb protein to inhibit E2F1-mediated transcription through synergy (18).…”

Section: Introductionmentioning

confidence: 91%

LIMD1 Increases the Sensitivity of Lung Adenocarcinoma Cells to Cisplatin via the GADD45α/p38 MAPK Signaling Pathway

Zeng

Wang

et al. 2020

Front. Oncol.

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Objective: To investigate the effect of LIM domain-containing protein 1 (LIMD1) on the sensitivity of lung adenocarcinoma cells to cisplatin and explore the mechanism. Methods: A549 and H1299 cells were transfected with lentivirus to establish LIMD1-overexpressing cell lines and their respective controls. The protein expression of DNA damage-inducible 45 alpha (GADD45α) and p38 mitogen-activated protein kinase (MAPK) was detected by Western blot. The survival of A549-vec, A549-LIMD1, H1299-vec, and H1299-LIMD1 cells after cisplatin treatment was observed by CCK-8, and the viability was calculated accordingly. Then, SB203580 was used to inhibit the activity of the p38 MAPK signaling pathway, after which the survival of A549-vec, A549-LIMD1, H1299-vec, and H1299-LIMD1 cells in response to cisplatin was observed again by CCK-8, and the viability was calculated accordingly. Results: When LIMD1 was overexpressed in A549 and H1299 cells, the levels of GADD45α and p-p38 MAPK were increased, but total p38 MAPK expression showed no significant change. After adding 30 µM cisplatin, the optical density (OD) values of A549-LIMD1 and H1299-LIMD1 cells were significantly lower than those of their respective controls at 24, 48, and 72 h. The viability of A549-LIMD1 and H1299-LIMD1 cells was significantly lower than that of their respective controls at all the times tested (p < 0.05). The Western blot results showed that the expression of apoptotic proteins cleaved caspase 3 and cleaved PARP in cisplatin-treated A549-LIDM1 and H1299-LIMD1 cells was significantly higher than that in their respective control cells. Flow cytometry showed that the apoptosis rates of A549-LIMD1 and H1299-LIMD1 cells were significantly higher than those of their respective controls (p < 0.05). SB203580 significantly inhibited the activation of the p38 MAPK signaling pathway in lung adenocarcinoma cells; however, neither the OD values nor the viability of A549-LIMD1 cells and H1299-LIMD1 cells showed no significant difference from those of their controls at 24, 48, and 72 h after cisplatin and SB203580 treatment (p > 0.05 for both). Western blot analysis showed that after SB203580 was added, the expression of cleaved caspase 3 and cleaved PARP in Zeng et al. LIMD1 Increases Sensitivity by GADD45α/p38 MAPK A549-LIMD1 and H1299-LIMD1 cells presented no significant difference compared with that in their respective controls. Conclusion: LIMD1 increases the sensitivity of lung adenocarcinoma cells to cisplatin by activating the GADD45α/p38 MAPK signaling pathway.

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“…50 Moreover, LIMD1 itself could be identified as a HIF-1 target gene mediating a negative regulatory feedback mechanism for hypoxic HIF-1α degradation. 36 Since LIMD1 is an XPO1 cargo substrate that accumulates in the nucleus upon LMB treatment and shuttles between both compartments, nuclear export inhibition could result in nuclear accumulation of LIMD1 and increased activity of the HIF-LIMD1 negative feedback mechanism. 51 Therefore, the effect of selinexor treatment on LIMD1 mRNA was investigated.…”

Section: Dovepressmentioning

confidence: 99%

“…The knowledge about the pattern of regulation of HIF was extended by a recent publication showing that the scaffold protein LIM Domain-Containing Protein 1 (LIMD1) is also involved in HIF-1 regulation in normoxia as well as in hypoxia. 36 LIMD1 was identified to be a HIF-1 target gene acting via a so far unknown negative feedback mechanism involving PHD2-LIMD1-VHL complex formation.…”

Section: Introductionmentioning

confidence: 99%

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

Depping

Fallois

Landesman

et al. 2019

OTT

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Purpose: The nucleocytoplasmic transport of macromolecules is critical for both cell physiology and pathophysiology. Exportin 1 (XPO1), the major nuclear export receptor, is involved in the cellular adaptation to reduced oxygen availability by controlling the nuclear activity of the hypoxia-inducible factors (HIFs). Recently, a specific inhibitor of XPO1, selinexor (KPT-330), has been identified that inhibits nuclear export of cargo proteins by binding to the XPO1 cargo-binding pocket. Patients and methods: We used different cancer cell lines from human tissues and evaluated the physiological activity of selinexor on the hypoxia response pathway in twodimensional (2D) monolayer cell cultures in quantitative real-time (qRT)-PCR experiments and luciferase reporter gene assays. A three-dimensional (3D) tumor spheroid culture model of MCF-7 breast cancer cells was established to analyze the effect of selinexor on 3D tumor spheroid structure, formation and viability. Results: Selinexor treatment reduces HIF-transcriptional activity and expression of the HIF-1 target gene solute carrier family 2 member 1 (SLC2A1). Moreover, 3D tumor spheroid structure, formation and viability are inhibited in response to selinexor-induced nuclear export inhibition. Conclusion: Here, we demonstrate the effect of specific XPO1-inhibition on the hypoxic response on the molecular level in 2D and 3D culture models of MCF-7 cells.

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A HIF – LIMD 1 negative feedback mechanism mitigates the pro‐tumorigenic effects of hypoxia

Cited by 18 publications

References 73 publications

miR-550a-5p Functions as a Tumor Promoter by Targeting LIMD1 in Lung Adenocarcinoma

miR-550a-5p Functions as a Tumor Promoter by Targeting LIMD1 in Lung Adenocarcinoma

LIMD1 Increases the Sensitivity of Lung Adenocarcinoma Cells to Cisplatin via the GADD45α/p38 MAPK Signaling Pathway

<p>The Nuclear Export Inhibitor Selinexor Inhibits Hypoxia Signaling Pathways And 3D Spheroid Growth Of Cancer Cells</p>

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