Original contributionMicroRNA 183 family profiles in pheochromocytomas are related to clinical parameters and SDHB expression☆,☆☆
Introduction
A neuroendocrine tumor that arises in the chromaffin cells in adrenal medulla is termed pheochromocytoma (PCC) [1]. Some PCCs are functioning tumors presenting with paroxysmal hypertension due to excess catecholamines produced by these tumors [2]. The incidence of PCC is around 2-5 patients per million per year with almost equal sex affinity, although some studies report a slight preference for females [3], [4]. Approximately 29 genes are known to be associated with PCC, and germline mutations in these genes are present in approximately 40% of PCCs, whereas the remaining 60% are considered to be sporadic in nature [3], [5], [6]. Despite the recent advancements in the field of molecular genetics, the exact mechanism involved in the tumorigenesis of PCC is still largely unknown [2]. There is also a lack of reliable predictive markers for PCC.
Recently, microRNA (miRNA) deregulation has been implicated in the pathogenesis of PCC [1], [7]. To date, only a few studies have examined miRNA expression profiling in PCCs (Table 1) [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Previous investigations have demonstrated that members of the evolutionarily conserved miR-183 cluster, which include miRNAs such as miR-96, miR-182, and miR-183, are abnormally expressed and are directly involved in the pathogenesis of various tumors, including neural crest–derived tumors [17]. In addition, miRNA-183 cluster members are reported to be involved in key cellular functions such as apoptosis, proliferation, and tumorigenesis [18]. Furthermore, deregulation of miR-183 cluster expression has downstream effects on succinate dehydrogenase enzyme subunit B (SDHB). SDHB is a major mitochondrial protein whose function is altered in the pathogenesis of hereditary PCCs [7].
The expression levels and clinicopathological implications of the whole miR-183 cluster family, as well as their effects on SDHB protein in human PCC tissues, have not been reported. Thus, in this study, we examined the expression of whole miRNA-183 family in patients with PCC. In addition, their associations with clinicopathological characteristics and SDHB protein expression were studied.
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Recruitment of tissues and sample selection
The patients who were chosen for this study had resection for PCCs between 1973 and 2015. They were operated on by surgeons from Hong Kong and Australia (C. Y. L. and V. L.). The patients were consecutively chosen with no selection bias. Ethical approval of this study has been obtained from the Griffith University human research ethics committee (GU ref. nos.: MED/19/08/HREC and MSC/17/10/HREC).
The resected PCC tissues were fixed in 10% formalin and embedded in paraffin wax. Histological
Downregulation of miR-182/96/183 and its correlation with clinicopathological parameters
Expressions of miR-182/96/183 were downregulated in many PCCs (Table 2). Approximately 90% (n = 45), 74% (n = 37), and 78% (n = 39) of PCCs showed either low or no expression (deletion) of miR-183, miR-182, and miR-96 levels, respectively.
In clinicopathological analysis, miR-96 low expression or deletion was significantly correlated with younger age. Patients with PCC aged ≤50 years exhibited high prevalence of miR-96 deletion when compared with patients >50 years (71% versus 29%, P = .01). Conversely,
Discussion
To the best of our knowledge, this is the first report on miRNA-183 cluster expressions in PCC. Abnormal regulation of the miR-183 cluster has been reported in many malignancies, including gastric, lung, bladder, endometrial, prostate, colon, and breast cancers [18]. Members of the miR-183 cluster show altered expression patterns (upregulation and downregulation) in different cancers [18], implying its varied and cell-specific function. Thus, it can function as either tumor suppressor or an
Acknowledgments
We would like thank the staff of Pathology Queensland and Ms Melissa Leung for their help in the laboratory work.
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Competing interests: All the authors of this paper declare that they have no conflict of interest.
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Funding/Support: The authors would like to thank the funding support of student scholarships from Griffith University and the project grants of the Menzies Health Institute of Queensland, Griffith University (GHI Project Grant Scheme 2012), Gold Coast, QLD, Australia. In addition, we would like to acknowledge the medical school scholarship from the Royal College of Pathologists of Australasia, Surry Hills, NSW, Australia for the support.