miR-210 的过表达与 SDH 相关的嗜铬细胞瘤、副神经节瘤和胃肠道间质瘤有关。

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

机构信息

Cancer Genetics Laboratory, Kolling Institute of Medical Research Department of Endocrinology, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales 2065, Australia Department of Surgery, Faculty of Medical and Health Sciences, Waikato Clinical School, University of Auckland, Auckland 1142, New Zealand Department of Anatomical Pathology, Cancer Diagnosis and Oncology Group, Kolling Institute of Medical Research Department of Endocrine and Oncology Surgery, Neurogenetics Research Laboratory, Kolling Institute of Medical Research Department of ENT Surgery, Department of Neurology Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, The University of Sydney, Sydney, New South Wales 2065, Australia.

出版信息

Endocr Relat Cancer. 2014 May 6;21(3):415-26. doi: 10.1530/ERC-13-0519. Print 2014 Jun.

DOI:10.1530/ERC-13-0519

PMID:24623741

Abstract

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 SDH-proficient) 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 (P=0.0016). miR-210 was higher in malignant than in unequivocally benign PC/PGLs (P=0.05), but significance was lost when benign and atypical tumours were combined (P=0.08). 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 SDH-proficient tumours (median 0.60; P=0.0078). 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 (P=0.001) under normoxia. Overall, our results suggest that SDH deficiency in PC, PGL and GISTs induces miR-210 expression and substantiates the role of aberrant hypoxic-type cellular responses in the development of these tumours.

摘要

miR-210 是对缺氧反应的关键调节因子。具有种系 SDHx 或 VHL 突变的嗜铬细胞瘤（PCs）和副神经节瘤（PGLs）具有假性低氧基因表达特征。我们假设含有 SDHx 或 VHL 突变的 PC/PGLs 和琥珀酸脱氢酶（SDH）缺陷的胃肠道间质瘤（GISTs）将相对于非 SDH 或非-VHL 突变的对应物过表达 miR-210。通过定量 PCR 分析了 i）根据基因型（一个 SDHA、五个 SDHB、七个 VHL、三个 NF1、七个 RET、15 个散发性、一个未知）和病理学（18 个良性、8 个非典型、11 个恶性、2 个未知）的 39 个 PC/PGLs 中的 miR-210；ii）根据 SDHB 免疫反应性（九个 SDH 缺陷和九个 SDH 有效）的 18 个 GISTs；和 iii）两个新的 SDHB 突变神经球细胞系中的 miR-210。与没有 SDHx 或 VHL 突变的肿瘤相比，SDHx 或 VHL 突变的 PC/PGLs 中的 miR-210 高 7.6 倍（P=0.0016）。与明确良性的 PC/PGLs 相比，恶性肿瘤中的 miR-210 更高（P=0.05），但当将良性和非典型肿瘤合并时，显著性丧失（P=0.08）。在多变量分析中，升高的 miR-210 与 SDHx 或 VHL 突变显著相关，但与恶性无关。在 GISTs 中，与 SDH 有效肿瘤（中位数 0.60；P=0.0078）相比，SDH 缺陷（中位数 2.58）的 miR-210 更高。在常氧条件下（P<0.01），与正常对照相比，含有 SDHB 突变的患者来源的神经球细胞系中的 miR-210 高 6.5 倍。此外，在 HEK293 细胞中，SDHB 的 siRNA 敲低在常氧条件下使 miR-210 增加 2.7 倍（P=0.001）。总的来说，我们的结果表明，PC、PGL 和 GIST 中的 SDH 缺陷诱导了 miR-210 的表达，并证实了异常低氧型细胞反应在这些肿瘤发展中的作用。