Identification of a Signaling Axis HIF-1α/MicroRNA-210/ISCU Independent of SDH Mutation That Defines a Subgroup of Head and Neck Paragangliomas

Merlo, Anna; Quirós, Sandra Bernaldo de; Secades, Pablo; Zambrano, Iriana; Balbı́n, Milagros; Astudillo, Aurora; Scola, Bartolomé; Arístegui, Miguel; Suárez, Carlos; Chiara, María‐Dolores

doi:10.1210/jc.2012-2410

Cited by 46 publications

(63 citation statements)

References 22 publications

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“…Although glycolysis is not as efficient for ATP generation, it is the fastest method of ATP production and requires the least energy for cell survival under oxidative stress conditions. Recent studies have revealed that the energy metabolism shift regulated by the miR-210-ISCU pathway is involved in many hypoxia-related physiologic and pathologic processes [45-47]. In our study, the downregulation of ISCU mRNA and protein levels after miR-210 transduction further supports the idea that ISCU is regulated by miR-210.…”

Section: Discussionsupporting

confidence: 85%

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

Sun

Zhao

Song

et al. 2017

Cell Physiol Biochem

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Background/Aims: The myocardial energy metabolism shift is one of the most important pathological features of ischemic heart disease (IHD). Although several microRNAs (miRs) are involved in the regulation of myocardial energy metabolism, their exact effects and underlying mechanisms remain unclear. The aim of this study was to investigate whether microRNA(miR-210) regulates the energy metabolism shift during oxidative stress in H9c2 cardiomyocytes. Methods: Cell survival was analyzed via CCK assay. The energy metabolism shift was detected by lactate assay, ATP assay and RT² profiler glucose metabolism PCR array. Protein and mRNA expression levels were determined by western blot and qPCR. We also used kits to detect the activity of Complex I, Sirt3 and the NAD⁺/NADH ratio. Results: We determined that miR-210 promoted the energy metabolism shift. The iron-sulfur cluster assembly protein (ISCU) was a target of miR-210. Additionally, we detected the activity of complex I and found that miR-210 inhibits mitochondrial respiration. Interestingly, miR-210 may also indirectly regulate SIRT3 by regulating ISCU. Conclusion: Our results confirm that miR-210 is essential and sufficient for modulating the cellular energy metabolism shift during H₂O₂-induced oxidative stress in H9c2 cardiomyocytes by targeting ISCU.

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Section: Discussionsupporting

confidence: 85%

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

Sun

Zhao

Song

et al. 2017

Cell Physiol Biochem

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“…In contrast, the NF1 and RET-mutated PC/PGLs in this study had miR-210 levels not different from normal adrenal medulla tissue, again consistent with the distinct, non-hypoxic gene expression signature previously described in these tumours (Dahia & Familial Pheochromocytoma 2006). Interestingly, a previous report showed miR-210 overexpression in parasympathetic PGL of the head and neck (HNPGLs) which was independent of germline SDH mutations (Merlo et al 2012), a finding which is consistent with more universal association of HNPGLs with hypoxic gene expression regardless of whether SDH deficiency is present or not. Our study did not include HNPGLs, and we cannot therefore state whether miR-210 is different in PGL arising from chief cells (HNPGLs) compared with chromaffin cells (sympathetic PGLs/PCs).…”

Section: Sdhb Knockdown Is Associated With Increased Mir-210 Levelssupporting

confidence: 91%

Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours

Tsang¹,

Dwight²,

Benn³

et al. 2014

Endocrine-Related Cancer

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miR-210 is a key regulator of response to hypoxia. Pheochromocytomas (PCs) and paragangliomas (PGLs) with germline SDHx or VHL mutations have pseudohypoxic gene expression signatures. We hypothesised that PC/PGLs containing SDHx or VHL mutations, and succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs), would overexpress miR-210 relative to non-SDH or -VHL-mutated counterparts. miR-210 was analysed by quantitative PCR in i) 39 PC/PGLs, according to genotype (one SDHA, five SDHB, seven VHL, three NF1, seven RET, 15 sporadic, one unknown) and pathology (18 benign, eight atypical, 11 malignant, two unknown); ii) 18 GISTs, according to SDHB immunoreactivity (nine SDH-deficient and nine SDHproficient) and iii) two novel SDHB-mutant neurosphere cell lines. miR-210 was higher in SDHx-or VHL-mutated PC/PGLs (7.6-fold) compared with tumours without SDHx or VHL mutations (PZ0.0016). miR-210 was higher in malignant than in unequivocally benign PC/PGLs (PZ0.05), but significance was lost when benign and atypical tumours were combined (PZ0.08). In multivariate analysis, elevated miR-210 was significantly associated with SDHx or VHL mutation, but not with malignancy. In GISTs, miR-210 was higher in SDH-deficient (median 2.58) compared with SDHproficient tumours (median 0.60; PZ0.0078). miR-210 was higher in patient-derived neurosphere cell lines containing SDHB mutations (6.5-fold increase) compared with normal controls, in normoxic conditions (P!0.01). Furthermore, siRNA-knockdown of SDHB in HEK293 cells increased miR-210 by 2.7-fold (PZ0.001) under normoxia. Overall, our results suggest that SDH deficiency in

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“…Mechanisms other than germline SDHx mutations, including mutations in as yet unidentified susceptibility gene(s) affecting SDH complex assembly/function, abnormal functional interactions with mitochondrial proteins, and/or epigenetic alterations, could be responsible for loss of protein expression (57,58). Another plausible explanation is that HIF1a accumulation due to impaired hydroxylation in hypoxic areas (59) might have resulted in downregulated SDHB expression either in an auto-regulatory loop (60) or through a putative signaling axis involving HIF1a/microRNA-210/iron-sulfur cluster scaffold protein (ISCU) (61).…”

Section: Discussionmentioning

confidence: 99%

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

Papathomas

Gaal

Corssmit

et al. 2014

European Journal of Endocrinology

119

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Objective: Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated. Design and methods: Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC. Printed in Great BritainPublished by Bioscientifica Ltd.Conclusions: These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDHx alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.

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Identification of a Signaling Axis HIF-1α/MicroRNA-210/ISCU Independent of SDH Mutation That Defines a Subgroup of Head and Neck Paragangliomas

Cited by 46 publications

References 22 publications

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

MicroRNA-210 Modulates the Cellular Energy Metabolism Shift During H2O2-Induced Oxidative Stress by Repressing ISCU in H9c2 Cardiomyocytes

Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

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