CrossMark
REVIEW
The role of microRNAs in the adrenocortical carcinomas
Xin Yu1 . Zheng Li2
Received: 26 November 2015 / Accepted: 10 December 2015
C International Society of Oncology and BioMarkers (ISOBM) 2015 ☐
Abstract MicroRNAs (miRNAs) are a group of small, non-protein-coding RNAs that inhibit gene expressions through binding their 3’-UTR regions. Each miRNA can regulate a number of target genes and play crucial roles in a lot of biological processes including organogenesis, hematopoiesis, cell development, proliferation, and inva- sion. Deregulated expression of miRNAs has been found to be associated with initiation and development of tumors. Increasing evidences showed that miRNAs play a crucial role in adrenocortical carcinomas (ACCs). Aberrant miRNA expression may contribute to ACC carcinogenesis, and it can act as tumor-suppressive or oncogenic miRNAs. In this review, we reviewed the recent studies available on ACC-associated miRNAs. We try to summarize the contribution of miRNAs to the initiation and development of ACCs.
Keywords Adrenocortical carcinomas . microRNAs . MiRNAs . MiR-7
Xin Yu and Zheng Li contributed equally to this work.
☒ Zheng Li kleeo@163.com
1 Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100042, China
2 Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100042, China
Introduction
Adrenal masses are frequent in humans, and a small subset of adrenal masses is malignant adrenocortical carcinomas (ACCs) [1-4]. ACCs are highly aggressive malignancy with an annual incidence of two cases per million adults [5-7]. Diagnosis of ACCs is challenging since it is difficult to dis- criminate ACCs from adrenocortical adenomas (ACAs) [5, 8, 9]. Currently, the Weiss system is the most common diagnos- tic criteria in ACCs [10, 11]. ACCs demonstrate high frequen- cy of metastatic spread, and therapeutic strategies are limited in [12, 13]. The prognosis for ACCs is poor with estimated 5- year survival rates of 30 % [7]. Therefore, the identification of diagnostic and therapeutic biomarkers of ACCs is urgent.
MicroRNAs (miRNAs) are a group of small (18 to 25 nucleotides), non-protein-coding RNAs that negatively regu- lated gene expression [14-17]. miRNAs exert their roles at the posttranscriptional level by inducing translational repression or target messenger RNA (mRNA) degradation [18-20]. Dys- regulation of miRNAs is observed in various disorders, prom- inently in malignancy [21, 22]. Increasing evidence has re- vealed that certain miRNAs function as oncogenes or tumor suppressors in various human cancers [23-25]. miRNAs play significant roles in various biological and pathological pro- cesses, including cell proliferation, apoptosis, and tumorigen- esis [26-28].
Deregulation of miRNAs in ACCs
Simultaneous miRNA and mRNA profiling identified six miRNAs that were significantly different expressed between normal adrenocortical tissues, benign adenomas, and adreno- cortical carcinomas (ACCs) [29]. Among them, miR-184 and miR-503 were statistically upregulated, while miR-511 and
miR-214 were statistically downregulated in ACCs than in other groups. In addition, miR-210 was significantly down- regulated in cortisol-secreting adenomas compared with that in ACCs. More importantly, the difference between dCTmiR- 511 and dCTmiR-503 (delta cycle threshold) distinguished ACCs from benign adenomas with high sensitivity and spec- ificity. In summary, miR biomarkers contribute to the differ- ential diagnosis of malignant ACCs.
Bimpak et al. demonstrated a total of 37 differentially expressed miRNAs in massive macronodular adrenocortical disease (MMAD) compared with normal tissues [30]. Among them, 16 miRNAs were downregulated and 21 miRNAs were upregulated. In addition, miR-130a and miR-382 can serve as potential diagnostic markers in MMAD. Moreover, miR-200b directly targeted Matrin 3 (MATR3) expression in an adreno- cortical cancer cell line (H295R).
Several miRNAs were distinctly expressed in ACC using microarray [31]. MiR-483-3p, miR-483-5p, miR-210, and miR-21 were upregulated, while miR-195, miR-497, and miR-1974 were downregulated in ACCs compared with adre- nal cortices and adenomas. Moreover, upregulation of miR- 195 or miR-497 and downregulation of miR-483-3p or miR- 483-5p decreased cell proliferation in human ACC cells. Fur- thermore, inhibition of miR-483-3p and overexpression of miR-195 or miR-497 induced cell death in ACCs. In addition, overexpression of miR-503, miR-1202, and miR-1275 signif- icantly correlated with shorter overall survival among patients with ACC.
A number of differentially expressed miRNAs were iden- tified in benign and primary malignant adrenocortical tumors using microarray profiling and directed quantitative RT-PCR analysis [32]. Among them, the expression levels of miR-100, miR-195, and miR-125b were significantly higher and miR- 483-5p was significantly lower in malignant ACCs than in benign tumors. Furthermore, miR-483-5p expression can ac- curately distinguish malignant tumors from benign tumors.
The expression profile of circulating miRNAs in adreno- cortical tumors (ACTs) was assessed in 25 preoperative plas- ma samples in patients with ACAs and carcinomas using mi- croarray and quantitative real-time PCR [33]. Among them, five (hsa-miR-100, hsa-miR-181b, hsa-miR-184, hsa-miR- 210, and hsa-miR-483-5p) were significantly overexpressed in ACCs compared with adenoma when normalized on hsa- miR-16 as a reference gene. Moreover, the combination of dCThsa-miR-210-dCThsa-miR-181b and dCThsa-miR-100/dCThsa-miR- 181b showed the highest diagnostic accuracy in ACAs. To conclude, circulating miRNAs are promising diagnostic and prognostic biomarker candidates of ACCs since the expres- sions of circulating miRNAs were significantly different. Fur- ther studies are required to evaluate their potential application on larger cohorts of patients.
Schmitz et al. assessed a total of 667 miRNAs using TaqMan low-density arrays to distinguish between benign
and malignant tumors [34]. They demonstrated that 59 miRNAs were upregulated and 89 miRNAs were downregu- lated in ACAs. Moreover, among them, three of the most significantly expressed single-key miRNAs distinguished ACAs from ACCs. Furthermore, miR-139-3p, miR-675, and miR-335 were significantly downregulated in ACCs. Upreg- ulation of miR-335 and miR-675 was observed in most cases with probable malignant courses. These data suggested that miR-675 and miR-335 contribute to the differentiation of ACCs from ACAs.
Doghman et al. identified a set of differentially expressed miRNA in childhood adrenocortical tumors (ACT) using mi- croarray [35]. These miRNAs included miR-99a and miR- 100. In addition, they regulated the expression of the insulin-like growth factor-mammalian target of rapamycin (mTOR)-raptor signaling pathway. Pharmacologic inhibition of mTOR signaling significantly inhibited tumor cell growth both in vitro and in vivo. These results indicate that miRNAs might involve in ACT through regulating mTOR signaling. Drugs that inhibit the mTOR pathway may provide a novel target for treatment of adrenocortical cancer.
Duregon et al. investigated the expression of five selected miRNAs, including miR-483-3p and 5p, miR-210, miR-195, and miR-1974, in a series of ACCs with different histologic variants, including classical, myxoid, and oncocytic carcino- mas. The expressions of miR-483-3p, miR-483-5p, and miR- 210 were significantly lower in oncocytic carcinomas than that in other histotypes. Moreover, high miR-210 was associ- ated with aggressive clinicopathologic parameters and shorter overall survival, including the presence of necrotic cells and high Ki-67 and glucose transporter 1.
Patel et al. observed higher expression levels of serum miR-34a and miR-483-5p in patients with ACC by quantita- tive reverse transcript polymerase chain reaction [36]. More- over, in vitro data demonstrated that miR-483-5p was highly expressed and is secreted into the supernatant in ACC cell line. It indicated that miR-483-5p was secreted via cellular exosomes, leading to high expression levels of miR-483-5p in the serum. In addition, apoptotic cell bodies during tumor necrosis may also result in high expression levels of miR-483- 5p in the serum. These results supported that miR-34a and miR-483-5p were dysregulated in human serum ACC. MiR- 34a and miR-483-5p may serve as novel serum biomarkers for differential diagnosis between benign and malignant adreno- cortical tumors (Table 1).
MiR-7
Glover et al. showed that microRNA-7-5p (miR-7) inhibited cell proliferation and resulted in cell cycle arrest in ACCs in vitro [37]. Overexpression of miR-7 could decrease ACC xe- nograft growth from ACC cell lines and primary ACC cells. In addition, Raf-1 proto-oncogene serine/threonine kinase
| Num | Method | Sample | Upregulated | Downregulated | Reference |
|---|---|---|---|---|---|
| 1 | Microarray PCR | Primary ACC tissues | miR-184, miR-503, miR-210, | miR-511, miR-214, miR-375 | 29 |
| 2 | Microarray RT-PCR | Primary ACC tissues | 16 miRNAs, miR-210, miR-484, miR-196a, miR-424, miR-491, miR-324-5p | 21 miRNAs, miR-200b, miR-203, miR-146b, miR-133 | 30 |
| 3 | Microarray RT-PCR | Primary ACC tissues | miR-483-3p, miR-483-5p, miR-210, miR-21 | miR-195, miR-497, miR-1974 | 31 |
| 4 | Microarray RT-PCR | Primary ACC tissues | miR-100, miR-195, and miR-125b | miR-483-5p | 32 |
| 5 | Microarray RT-PCR | ACC serum | miR-100, miR-181b, miR-184, miR-210, miR-483-5p | 33 | |
| 6 | Microarray RT-PCR | Primary ACC tissues | 59 miRNAs, miR-335, miR-675 | 89 miRNAs, miR-139-3p, miR-675, miR-335 | 34 |
| 7 | Microarray RT-PCR | Primary childhood ACC tissues | miR-210 | 35 | |
| 8 | RT-PCR | ACC serum | miR-483-5p, miR-34a | 36 |
(RAF1) and mechanistic target of rapamycin (mTOR) were proved to be the direct targets of miR-7. More importantly, overexpression of miR-7 inhibited cyclin-dependent kinase 1 (CDK1) in vivo. CDK1 was upregulated in ACC patient sam- ples, and its expression was inversely related with miR-7. To conclude, miR-7 decreases ACC growth through inhibiting several oncogenic pathways. These researches provide that miR-7 might be a potential target for replacement therapy in ACC.
MIR-195
Previous study showed that miR-195 was downregulated in ACCs and thyroid cancer and miR-195 played a tumor- suppressive function by regulating cell proliferation and apo- ptosis in cancer [32]. Zinc finger protein 367 (ZNF367) be- longs to the zinc finger protein family. ZNF367 is absent in adult tissue in normal condition. Jain et al. showed that ZNF367 was overexpressed in ACCs compared to normal tissue and benign tumors [38]. In addition, functional experi- ments demonstrated that ZNF367 reduced cellular prolifera- tion, invasion, migration, and adhesion to extracellular pro- teins both in vitro and in vivo. Moreover, miR-195 expression levels were inversely correlated with ZNF367 expression levels using integrated gene and miRNA expression analyses. Furthermore, miR-195 regulates cellular invasion and directly regulates ZNF367 expression. Therefore, miR-195 might play a role in cancer progression through regulating ZNF367.
MiR-483-3p
Wang et al. showed that miR-483-3p was overexpressed in 68 % of ACCs compared to 12 % of adrenocortical adenomas (ACAs) [39]. A combination of miR-483-3p and Smad4 com- plements the Weiss score and improved diagnostic accuracy in the diagnosis of ACC in borderline tumors. In conclusion, miR483-3p and Smad4 expressions help to differentiate ACCs and ACAs. In addition, another study showed that miR-483-3p was upregulated in ACCs and downregulation of miR-483-3p decreased cell proliferation in human ACC cells [31]. Duregon et al. found that the expression of miR- 483-3p was significantly lower in oncocytic carcinomas than that in other histotypes [35]. The expression level of p53 up- regulated modulator of apoptosis (PUMA) was significantly downregulated in ACCs and inversely correlated with miR- 483-3p expression. Therefore, PUMA might be a potential target of miR-483-3p in ACCs. This data suggested that miR-483-3p played an oncogenic role in the pathogenesis of ACCs (Table 2).
MiRNAs predict ACC prognosis
Local or distant recurrences of ACCs often occur in tumors named as “aggressive” ACC (aACC), which is opposed to the “non-aggressive” ACC (naACC) [40, 41]. Chabre et al. inves- tigated the predictive value of tissue and serum miRNAs as
| Name | Upregulation or downregulation | Target gene | role | Reference |
|---|---|---|---|---|
| miR-7 | Down | Raf-1, RAF1, mTOR | Tumor suppressor | 37 |
| miR-195 | Down | ZNF367 | Tumor suppressor | 32 |
| miR-483-3p | Up | PUMA | Oncogene | 31, 35, 39 |
prognostic markers of ACCs [42]. They showed that the ex- pression levels of miR-195 and miR-335 were significantly lower in both tumor samples and serum samples of ACC compared with ACA or HC. In addition, the expression levels of miR-139-5p and miR-376a were markedly higher in aACC than in naACC patients in tumor samples, but not in serum samples. The expression of miR-483-5p was significantly in- creased in most tissue samples of ACC relative to ACA pa- tients or HC, and the expression of serum miR-483-5p was only detected in aACC patients. More importantly, high serum miR-483-5p levels or low serum miR-195 levels were associ- ated with poor prognosis, which was demonstrated as shorter recurrence-free survival and overall survival. This result dem- onstrated that serum miR-483-5p and miR-195 may serve as potential predictive biomarkers to evaluate the clinical out- come in patients with ACC.
Decreased expression of DICER1 was associated with poor clinical outcome in many malignant tumors. DICER1 e TRBP protein expression was assessed in adult adrenocortical tu- mors [43]. Overexpression of DICER1 gene was more fre- quently observed in ACCS than in ACAs. Moreover, the fre- quency of a weak DICER1 expression was higher in metasta- tic ACCs compared with that in non-metastatic ACCs. A weak DICER1 expression was associated with reduced overall and disease-free survivals in ACCS, serving as an independent predictor of cancer recurrence. In summary, a weak DICER1 protein expression was significantly correlated with reduced disease-free and overall survivals, indicating its role as a promising predictor of cancer recurrence in ACCs.
Mechanisms of deregulation of miRNAs in ACCs
The miRNA-processing genes, including TARBP2 DROSHA, DICER (DICER1), DGCR8, and PRKRA, are the critical genes in the biogenesis of miRNA [44]. The ex- pressions of TARBP2, DICER, and DROSHA were signifi- cantly higher in the ACCs compared with ACAs or adrenal cortices [45]. TARBP2 might serve as a strong biomarker to differentiate carcinomas from adenomas. Furthermore, inhibited expression of TARBP2 reduced cell proliferation and promoted cell apoptosis in human ACC cell line. More importantly, miR-195 and miR-497 targeted and regulated the expression of TARBP2 and DICER directly in ACC cells. Therefore, the deregulated miRNA-processing genes might result in deregulation of miRNAs in adrenocortical tumors.
Acknowledgments This work was supported by grants from the Na- tional Natural Science Foundation of China (NSFC) (Grant Number: 81401847).
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