MicroRNAs and Target Genes in Pituitary Adenomas

Review Feng Yajuan et al. MicroRNAs and Target Genes … Horm Metab

Res 2017; 00: 00–00

MicroRNAs and Target Genes in Pituitary Adenomas

Authors Yajuan Feng1 * , Zhi-gang Mao2*, Xin Wang1, Qiu Du1, Mengyao Jian1, Dimin Zhu2, Zheng Xiao2, Hai-jun Wang2, Yong-hong Zhu1

Key words miRNA, pituitary adenoma, pituitary gland, target genes received 06.09.2017 accepted 15.11.2017 Bibliography DOI https://doi.org/10.1055/s-0043-123763 Published online: 19.1.2018 Horm Metab Res 2018; 50: 179–192 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence Hai-jun Wang Department of Neurosurgery and Pituitary Tumor Center The First Affiliated Hospital of Sun Yat-sen University No. 74, Zhongshan Road 2 Guangzhou 510080 China Tel.: + 86 20 87332323 [email protected]

Yong-hong Zhu Department of Histology and Embryology Zhongshan School of Medicine Sun Yat-sen University No.74, Zhongshan Road 2 Guangzhou 510080 China Tel.: + 86 20 87332323 [email protected] Downloaded by: Thieme Gruppe. Copyrighted material.

Affiliations 1 Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong Province, China 2 Department of Neurosurgery and Pituitary Tumor Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong Province, China

Abs tr ac t Pituitary adenomas account for the top three primary intracranial tumors in terms of total incidence rates. The clinical symptoms presented by the disease are often characterized by a series of systemic endocrine disorders, severe occupational lesions, and even some malignant features, and therefore early diagnosis and predicting recurrence would be instructive for clinical treatment of pituitary adenomas. An increasing number of specific microRNA (miRNA) expression signatures have been identified in pituitary, and miRNAs are related with the pituitary tumorigenesis, dysfunction, neurodegeneration, and metastatic non-functioning pituitary carcinoma. Here, this paper reviews the effects of aberrant miRNA expression in human pituitary adenomas and summarizes some corresponding target genes and biological significance over the last 7 years (2010–2017).

Abbreviations

Introduction

miRNAs GH ACTH PRL TSH FSH LH mRNAs UTRs

Pituitary adenomas account for the top three primary intracranial tumors in terms of total incidence rates (~10–15 %) [1, 2], making it one of the most common forms of intracranial tumors. Ongoing improvements in diagnostic technology have shown a rising trend in the incidence rates of this disease. Its clinical symptoms are often characterized by a series of systemic endocrine disorders, such as Cushing’s syndrome and acromegaly. In addition to the clinical manifestation of endocrine disorders, pituitary adenomas also cause other adverse effects on surrounding brain tissues, possibly leading to visual impairment, headaches, and so on. A type of malignant pituitary adenoma has been reported to give rise to a tumor that infiltrates the sella turcica and invades surrounding brain structures. Although this tumor can be excised by surgical methods, it

MicroRNAs Growth hormone Adrenocorticotrophic hormone Prolactin Thyroid-stimulating hormone Follicle-stimulating hormone Luteinizing hormone Messenger RNAs Untranslated regions

* These authors contributed equally to this work

Feng Y et al. MicroRNAs in Pituitary Adenomas … Horm Metab Res 2018; 50: 179–192

179

is difficult to remove completely and can relapse easily. Therefore, early diagnosis and predicting recurrence would be instructive for clinical treatment of pituitary adenomas. MicroRNAs (miRNAs) serve as post-transcriptional markers of gene expression [3, 4] and form base pairs with target messenger RNAs [5, 6] at the 3′,5′-untranslated regions or within the coding sequence [7, 8], whose differential expression signature is a hallmark of human cancers and has been identified in various human tumors [9, 10], such as the prostate [11–13], ovary [14, 15], lung [16–18], breast [19, 20], brain [21, 22], stomach [23–25], liver [26, 27], and pituitary [6, 28, 29]. Depending on corresponding cellular contexts and target genes [30, 31], miRNAs are related with pituitary tumorigenesis [32], dysfunction, neurodegeneration [33], and metastatic non-functioning pituitary carcinoma [34]. Currently, more and more target genes have been validated in specific human pituitary adenoma samples. Here, this paper reviews the effects of aberrant miRNA expression in human pituitary adenomas and summarizes some corresponding target genes, biological significance over the last 7 years (2010–2017).

Tumor Classification Generally, pituitary adenomas are divided into functional and non-functional pituitaryadenomas, based on their ability to secrete excessive pituitary hormones. According to the type of hormone secreted by the tumor, pituitary adenomas can be divided into: growth hormone (GH)-secreting pituitary adenomas, adrenocorticotrophic hormone (ACTH)-secreting pituitary adenomas, prolactin (PRL)-secreting pituitary adenomas/prolactinomas, non-functioning pituitary adenomas (NFPAs), thyroid-stimulating hormone (TSH)-secreting pituitary adenomas, gonadotrophin-secreting pituitary adenomas [follicle-stimulating hormone (FSH), and luteinizing hormone (LH)] [2]. According to different tumor types, this paper summarizes the abnormal expression of miRNAs, target genes, and biological significances as shown below (▶Fig. 1).

miRNAs in GH-Secreting Pituitary Adenomas In our research group, previous studies [35] have shown that 52 miRNAs with different expression levels in GH-secreting pituitary adenomas when compared to normal pituitary glands: 23 miRNAs were upregulated (miR-136, miR-15b, miR-184, miR-194, miR200c, miR-297, miR-29b-1, miR-32, miR-340, miR-365, miR-378, miR-486-5p, miR-491-3p, miR-519d, miR-525-5p, miR-551a, miR574-5p, miR-657, miR-662, miR-768-3p, miR-885-5p, miR-890, miR-96) and 29 miRNAs (miR-125b, miR-126, miR-145, miR-17, miR-185, miR-192, miR-193a-3p, miR-193a-5p, miR-200b, miR302c, miR-30a, miR-30b, miR-31, miR-381, miR-490-5p, miR-503, miR-510, miR-542-3p, miR-552, miR-553, miR-612, miR-617, miR622, miR-625, miR-637, miR-654-3p, miR-769-5p, miR-801, miR99b) were downregulated; miR-125b, miR-524-5p and miR-125a5p were linked to the chain precursor of the target genes IGFBP-3 (insulin-like growth factor binding protein-3) and IGFALS (insulin-like growth factor binding protein, acid labile subunit), which

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play a crucial role in protein binding, receptor binding, cell communication, and regulation of growth; miR-126 and miR-381 targeted PTTG1 (pituitary tumor-transforming 1), where miR-126 was believed to be involved in the development of tumor growth hormone; miR-516b and miR-96 targeted IGFBP-7; miR-744 targeted IGFBP6 and miR-99b targeted PROP1 (homeobox protein prophet of Pit1), where both the IGFBP-6 and PROP1 were related to organ development, nucleic acid binding and membrane bound organelles. MiR-124 targeted Sarcoplasmic calcium-binding protein 1(SCP1)3′UTR directly and inhibited SCP1 expression, and miR-145 targeted the insulin receptor substrate-1(IRS-1) and miR-151-3p targeted the insulin receptor substrate-4 (IRS-4), which regulated cell communication, receptor and membrane activities. Moreover, further researches have shown that the marine compound SZ-685C induced apoptosis of MMQ cells by downregulating miR-200c, suggesting that it could be used as a therapeutic agent for pituitary adenomas [36]. MiR-200c was known to be overexpressed in GH3 and MMQ cells and it regulated pituitary apoptosis through the PTEN (phosphatase and tensin homologue)/AKT signaling pathway [37]. Palumbo et al. [38] demonstrated 17 miRNAs to be differentially expressed in GH-producing pituitary tumors; among these miRNAs, miR-26b, miR-26a, miR-107, miR-212, and miR-103 were found to be upregulated, whereas miR-144, miR-164, miR-145, miR-125b, miR-141, miR-143, miR-15b, miR-16, let-7b, let-7a3, and miR-128 were downregulated. MiR-128 targeted BMI1 and miR-26b directly controlled the PTEN/AKT signaling pathway, in turn regulating the tumorigenicity and invasion of pituitary cells, thereby affecting the formation of pituitary tumors, miR-26b was also found to target EPHA2 [39], which is suspected to be relevant to early embryonic development, pituitary hormone secretion, and other reproductive functions; lymphoid enhancer-binding factor 1 (LEF-1) was also determined as another target gene of miR-26b, which is believed to be involved in the anterior pituitary development [40]. Base on that, it can be deduced that miR-26b may control multiple target genes to form a multivariate network and play an important role in tumor development and progression. Similarly, a study conducted by Liang et al. [41] demonstrated that overexpression of miR-655, miR-300, miR-381 and miR-329 suppressed the viability and proliferation of human pituitary tumor cells and regulated the PTTG1 expression. Palmieri et al. [42] reported high mobility group AT-hook (HMGA)-targeting miRNAs such as miR-15, miR-16, miR-26a, let-7a, and miR-196a2 were downregulated in pituitary adenomas, and all these HMGA-targeting miRNAs inhibited the proliferation of GH3 and contributed to pituitary tumorigenesis. D'Angelo et al. demonstrated that some downregulated miRNAs(miR-34b, miR-326, miR-633, miR-432, miR-374b, miR-548c-3p, miR-570 and miR-603) correlated with the development of pituitary tumors, miR-326, miR-570 and miR432 targeted HMGA2; miR-34b and miR-548c-3p targeted HMGA1 and HMGA2; miR-603 and miR-326 targeted E2F1 (E2F transcription factor 1) [43], E2F coordinates mitotic genes, targeting hPTTG1, may be the basis of the pituitary tumorigenesis [44]. Currently, increasing evidence indicated that aberrantly-expressed HMGAs are related to tumor initiation, promotion and progression [45, 46]. These downregulated miRNAs were acted as negative regulators of HMG families gene expression, and were required for pituitary tumorigenesis. Feng Y et al. MicroRNAs in Pituitary Adenomas … Horm Metab Res 2018; 50: 179–192

Downloaded by: Thieme Gruppe. Copyrighted material.

Review


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▶Fig. 1 The abnormal expression of microRNAs (miRNAs), target genes and biological significances in pituitary adenomas.

Review

▶Table 1 List of MicroRNAs in GH-secreting pituitary adenomas. MiRNA

Expression

Number Tumor

Normal

Target genes

Biological Significance

Mao et al. [35]

miR-744

2.03

21

6

IGFBP-6

Regulates the organ development, nucleic acid binding, and membrane bound organelles

Mao et al. [35]

miR-96

2.38

21

6

IGFBP-7


Mao et al. [35]

miR-516b

0.64

21

6

IGFBP-7


Mao et al. [35]

miR-125b/524-5p/125a-5p

0~1

21

6

IGFBP3, IGFALS

Protein binding, receptor binding, cell communication, and regulation of growth

Palumbo et al. [38]

miR-125b

↓

/

/

/

/

Mao et al. [35]

miR-126

0.39

21

6

PTTG1

Influences the development of GH-secreting pituitary adenomas

Mao et al. [35]

miR-145

0.42

21

6

IRS-1

Regulates cell communication, receptor, and membrane activities

Palumbo et al. [38]

miR-145

↓

/

/

/

/

Mao et al. [35]

miR-151-3p

↓

/

/

IRS-4


Mao et al. [35]

miR-185

0.25

21

6

/

/

Fan et al. [48]

miR-185

↑

20

7

SSTR2

Promotes the cell proliferation and reduce the apoptosis of GH3 cells

Mao et al. [35]

miR-136/184/194/297/29b-1/32/ 340/365/378/486-5p/491-3p/ 519d/525-5p/551a/574-5p/657/ 662/768-3p/885-5p/890

↑ > 2

21

6

/

/

Mao et al. [35]

miR-17/192/193a-5p/200b/302/ 30a/30b/31/381/490-5p/503/510/ 542-3p/552/553/612/617/622/ 625/637/654-3p/769-5p/801

0`1

21

6

/

/

Mao et al. [35]

miR-99b

0.32

21

6

PROP1

Regulates organ development, nucleic acid binding, and membrane bound organelles

Denes et al. [54]

miR-34a

↑

/

/

AIP

/

Trivellin et al. [55], Palumbo et al. [38]

miR-107

2.5

11

10

AIP

A tumor suppressor

Mao et al. [35] Chen et al. [36]

miR-200c

↑

/

/

PTEN/Akt

Plays an oncogenic role in pituitary adenoma cells

Palumbo et al. [38]

miR-144/164/141/143,Let-7a3

↓

/

/

/

/

Palumbo et al. [38]

miR-128

↓

/

/

BMI1

Influences the tumorigenicity and invasive of pituitary cells

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Reference

▶Table 1 Continued. List of MicroRNAs in GH-secreting pituitary adenomas. MiRNA

Expression

Number Tumor

Normal

Target genes


Yuan et al. [39]

miR-26b

↑

/

/

EphA2

Participates in Early embryonic development, pituitary hormone secretion, and other reproductive functions

Palumbo et al. [38]

miR-26b

↑

/

/

PTEN/Akt

Zhang et al. [40]

miR-26b

/

/

/

LEF-1

Participates in the anterior pituitary development

Palumbo et al. [38]

miR-212/103

↑

/

/

/

/

Liang et al. [41]

miR-655/300/381/329

↑

16

4

PTTG1

Decreases cell motility in vitro and induces apoptosis in GH3 and MMQ cells

Renjie and Haiqian [57], Mussnich et al. [63]

miR-15

↓

16

/

Sox5, HMGA1, HMGA2

Tumor suppressor, inhibits the tumor cell proliferation, invasion and migration

Mao et al. [35]

miR-15b

4.29

21

6

/

/

Palumbo et al. [38]

miR-15b

↓

/

/

/

/

D'Angelo et al. [43]

miR-34b/548c-3p

↓

12

3

HMGA1, HMGA2

Affects the G1-S transition of the cell cycle progression

Mussnich et al. [63]

miR-26a/196a2

↓

9

/

HMGA1, HMGA2

Negatively regulates pituitary cell proliferation

Palumbo et al. [38], Mussnich et al. [63], Renjie and Haiqian [57]

miR-16

↓

9

/

HMGA1, Sox5

Tumor suppressor, inhibits the tumor cell proliferation, invasion and migration


Let-7a

↓

9

/

HMGA2



miR-326

↓

12

3

HMGA2,E2F1



miR-570/432

↓

12

3

HMGA2



miR-374b/633

↓

12

3

/


Leone et al. [47]

miR-23b

↓

15

5

HMGA2

Inhibits cell proliferation

Leone et al. [47]

miR-130b

↓

15

5

CCNA2

Inhibits cell proliferation

Palumbo et al. [38]

Let-7b

↓

/

/

/

/


miR-320

↑

12

3

/

/


miR-603

↓

12

3

E2F1


Expression: ↑: Increase; ↓: Decrease. Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in normal pituitary glands; Number: The number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article. IGFBP-6: Insulin-like growth factor binding protein-6; IGFBP-7: Insulin-like growth factor binding protein-7; IGFBP3: Insulin-like growth factor binding protein-3; IGFALS: Insulin-like growth factor binding protein, acid labile subunit; PTTG1: Pituitary tumor-transforming 1; IRS-1: Insulin receptor substrate 1; IRS-4: Insulin receptor substrate 4; SSTR2: Somatostatin receptor 2; PROP1: Homeobox protein prophet of Pit-1; AIP: Aryl hydrocarbon receptor interacting protein; PTEN/Akt: Phosphatase and tensin homologue/AKT serine/threonine kinase 1; BMI1: BMI1 proto-oncogene, polycomb ring finger; EphA2: Ephrin receptor A2; LEF-1: Lymphoid enhancer-binding factor 1; Sox5: SRY (sex determining region Y)-box 5; HMGA1: high mobility group AT-hook 1; HMGA2: High mobility group AT-hook 2; E2F1: E2F transcription factor 1; CCNA2: Cyclin A2.


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Reference

Review

▶Table 2 List of MicroRNAs in ACTH-secreting pituitary adenomas.

MiRNA

Target genes

Expression Tumor

Normal


Amaral et al. [56]

miR-145

2

11

7

/

/

Amaral et al. [56]

miR-21

2.4

11

7

/

/

Amaral et al. [56]

miR-141

2.6

11

7

/

/

Amaral et al. [56]

let-7a

3.3

11

7

/

/

Amaral et al. [56]

miR-150

3.8

11

7

/

/

Amaral et al. [56]

miR-15a

4.5

11

7

/

/

Amaral et al. [56]

miR-16

5

11

7

/

/

Renjie and Haiqian [57]

miR-16/132/15a

↓

16

/

Sox5

A tumor suppressor

Amaral et al. [56]

miR-143

6.4

11

7

/

/

Stilling et al. [58]

miR-122

10.793

2

6

/

/


miR-923/10b/1238/30c-1 * /486-3p/ 1248/1303/208b/566/663

↑ > 3

8

7

/

/


HS_29

6.604

8

7

/

/


HS_305_b

4.655

8

7

/

/


HS_22.1

4.053

8

7

/

/


solexa-8048-104

3.46

8

7

/

/


miR-450b-5p/323-5p/136 * / 411 * /132 * /431 * /212/542-5p/ 1181/424 * /129 * /542-3p/508-5p/ 513a-5p/509-5p/31/129-3p/510

↓ –3 to 10

8

7

/

/


solexa-2502-366

–4.419

8

7

/

/


solexa-3126-285

–5.212

8

7

/

/


miR-493

–4.571

8

7

LGALS3, RUNX2

Regulates proliferation and apoptosis


miR-513:9.1

–7.698

8

7

/

/


miR-513c/507/508-3p/513a-3p / 31 * /506/551b/509-3p/513b

↓ > –10

8

7

/

/


miR-509-35p/514

↓ > –20

8

7

/

/

Gentilin et al. [59]

miR-26a

3

/

/

PRKCD

Affects G1/S transition


miR-181b

↑

/

/

/

/


miR-124a/191/212/24

↓

/

/

/

/

Garbicz et al. [61]

miR-93-3p/25-3p/93-5p/106b-5p

↑

25

/

MCM7

/

Expression: ↑: Increase; ↓: Decrease Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in normal pituitary glands; Number: The number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article Sox5: SRY (sex determining region Y)-box 5; IGFALS: Insulin-like growth factor binding protein, acid labile subunit; RUNX2: Runt related transcription factor 2; PRKCD: Protein kinase C delta; MCM7: Minichromosome maintenance complex component 7

Moreover, some miRNAs, such as miR-23b and miR-130b [47], were demonstrated to inhibit cell proliferation in GH-secreting pituitary adenomas, while some other miRNAs enhanced cell proliferation. For instance, the upregulation of miR-185 inhibited the apoptosis of GH3 cells [48]. Meanwhile, it has been suggested that aryl hydrocarbon receptor-interacting protein (AIP) gene, a tumor susceptible gene [49, 50], mediated cellular response to various

184

compounds and regulated cell proliferation via the cAMP pathways. The lack of AIP was closely related to the occurrence of pituitary adenoma [51, 52] and was commonly found in patients with acromegaly and gigantism [53]. It was demonstrated that miR-34a [54] bound to AIP-3′ UTR and was overexpressed in low AIP-protein expression of somatotropinomas that displayed an invasive phenotype and resistance to somatostatin analogs (SSAs). The overexFeng Y et al. MicroRNAs in Pituitary Adenomas … Horm Metab Res 2018; 50: 179–192


Number Reference

▶Table 3 List of MicroRNAs in PRL-secreting pituitary adenomas. Number


MiRNA

Expression

miR-320

↓

Target genes Tumor

Normal

6

3

/


/


miR-603

↓

6

3

E2F1

Affects G1-S transition


miR-34b/548c-3p

↓

6

3

HMGA1, HMGA2



miR-326

↓

6

3

HMGA2, E2F1



miR-570/432

↓

6

3

HMGA2


Chen et al. [62]

miR-432/342-3p/23b/ 493/493( * )/664( * )

↑

/

/

/

/

D'Angelo et al.[43]

miR-633/374b

↓

6

3

/



miR-15/26a/196a2

↓

9

/

HMGA1, HMGA2



miR-16

↓

9

/

HMGA1



Let-7a

↓

9

/

HMGA2



miR-410

–0.077

/

/

CCNB1

/

Roche et al. [64]

miR-183

↓

/

/

KIAA0101

Inhibits tumor cell proliferation

Chen et al. [62]

miR-200b/199b-3p/125b

↓

/

/

/

/

Expression: ↑: Increase; ↓: Decrease. Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in normal pituitary glands; Number: The number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article. E2F1: E2F transcription factor 1; HMGA1; High mobility group AT-hook 1; HMGA2: High mobility group AT-hook 2; CCNB1: Cyclin B1.

pression of miR-107 [55] acted as a tumor suppressor, which also targeted AIP. Therefore, we can deduce that multiple miRNAs can co-modulate the expression of AIP and interact with each other, forming co-targeting networks. However, further research needs to be conducted to confirm whether miR-34a, miR-107 and any other miRNAs can be combined as a complex tumor suppressor to mediate AIP and transduce cell proliferation, thus forming a novel therapeutic target. miRNAs in GH-secreting pituitary adenomas are summarized in ▶Table 1.

miRNAs in ACTH-Secreting Pituitary Adenomas The downregulation of miRNAs, such as miR-145 (2.0-fold), miR21 (2.4-fold), miR-141 (2.6-fold), let-7a (3.3-fold), miR-150 (3.8fold), miR-15a (4.5-fold), miR-16 (5.0-fold), and miR-143 (6.4-fold), has been reported in corticotropinomas when compared to normalpituitaries [56]. Owing to the tumor suppressing characteristic of miR-15a, miR-16, and miR-132, pituitary tumor cell proliferation, invasion, and migration were inhibited by directly targeting Sox5 [SRY (sex determining region Y)-box 5] [57].


Stilling [58] demonstrated that 47 miRNAs underwent significant fold change ( > 3) among the studied miRNAs. Upregulation of miRNA-122 (10.793-fold) and miRNA-493 (–4.571-fold) was observed in adenomas when compared with normal pituitaries. Additionally, the study found that miR-493 was upregulated (3.465-fold) in carcinomas compared to that in ACTH adenomas, while miR-122 was prominently upregulated (14.30-fold) in both ACTH adenomas and carcinomas. Gentilin et al. [59] discovered that miR-124a, miR191, miR-212, and miR-24 were downregulated and miR-181b, miR26a were upregulated; miR-26a was the most upregulated miRNA ( + 300 % vs. normal pituitary), which targeted PRKCD (protein kinase C delta) and was involved in the downregulation of cyclin E and cyclin A expression. It was reported that PRKCD [60] suppressed the proliferation of ACTH-secreting pituitary adenoma cells; hence, it was considered as a new therapeutic approach for the treatment of persistent and recurrent Cushing's disease. MiR-93-3p, miR-25-3p, miR-93-5p, and miR-106b-5p, acting on MCM7 (minichromosome maintenance complex component 7), were found to be overexpressed in invasive ACTH adenomas, leading to increased invasiveness and unfavorable outcomes after resection [61]. miRNAs in ACTH-secreting pituitary adenomas are summarized in ▶Table 2.

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Reference

Review

▶Table 4 List of MicroRNAs in NF-secreting pituitary adenomas. MiRNA

Number

Expression

Tumor

Target genes


Normal

Trivellin et al. [55]

miR-107

3.5 ± 0.97

24

10

AIP

Wu et al. [65]

miR-598/181d/191-3p/ 181b-5p/3676-5p/383

↑

20

/

/

A tumor suppressor

Leone et al. [47]

miR-23b

↓

21

5

HMGA2

/

Leone et al. [47]

miR-130b

↓

21

5

CCNA2

/

Butz et al. [66]

miR-424/503

↓

80

14

CDC25A

/

Butz et al. [67]

miR-135a/429/140-5p/ 582-3p/938/582-5p

↑

10

10

Smad3

/

Butz et al. [67]

miR-197/33b

↑

10

10

DLK1

/


miR-15/16/26a/196a2, Let-7a

↓

18

/

HMGA1, HMGA2

/

Wang et al. [68]

miR-133

↓

/

FOXC1

/

Wei et al. [34]

miR-20a/17-5p

↑

8

/

PTEN, TIMP2

Influences pituitary carcinoma metastasis

Wang et al. [68]

miR-106b

↑

8

/

PTEN, TIMP2

Influences pituitary carcinoma metastasis

Wei et al. [34]

miR-106b

↑

20

10

PTEN-PI3K/AKT

Affects migration and invasion of pituitary adenoma cells

Liang et al. [70]

miR-124a

38.58

10

2

/

/

Liang et al. [70]

miR-144/373/422b/202/520e/32/ 422a/181c/181b/520c/188/155/ 520 f/520b/182/10b/523/146a

> 3.0

10

2

/

/

Liang et al. [70]

PREDICTED MIR240/207/220/112/206/166

↑ 3–6

10

2

/

/

Liang, et al. [70]

miR-31/506/218/503/513/514

↓ > 10-fold

10

2

/

/

Butz et al. [71]

miR-128a/516a-3p/155

↑

27

15

Wee1

DNA damage accumulates

Butz et al. [71]

miR-195

1.45

27

15

/

/

Butz et al. [71]

miR-20a/93

↑

27

15

/

/

Zhen et al. [72]

miR-524-5p

↓

20

8

PBF

Regulates the biological properties of PDFS cells

Expression: ↑: Increase; ↓: Decrease. Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in normal pituitary glands; Number: The number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article. AIP: Aryl hydrocarbon receptor interacting protein; HMGA2: High mobility group AT-hook 2; CCNA2: Cyclin A2; CDC25A: Cell division cycle 25A; Smad3: SMAD family member 3; DLK1: Delta like non-canonical Notch ligand 1; HMGA1; High mobility group AT-hook 1; HMGA2: High mobility group AT-hook 2; FOXC1: Forkhead box C1; TIMP2: TIMP metallopeptidase inhibitor 2; PTEN/Akt: Phosphatase and tensin homologue/AKT serine/ threonine kinase; Wee1: Wee1 kinase; PBF: PTTG1 (pituitary tumor-transforming 1) interacting protein.

miRNAs in PRL-Secreting Pituitary Adenomas (Prolactinomas) Chen et al. found that 6 miRNAs(miR-23b, miR-664, miR-432, miR493, miR-493 * , miR-342-3p) were upregulated and 4 miRNAs(miR-125b, miR-200b, miR-130a, miR-199b-3p) were downregulated in prolactinomas [62]. D'Angelo et al. [43] demonstrat-

186

ed that miR-34b, miR-326, miR-633, miR-432, miR-374b, miR-548c-3p, miR-570, miR-320 and miR-603 were downregulated in prolactinomas. Three miRNAs(miR-326, miR-570 and miR432) targeted HMGA2, miR-34b and miR-548c-3p targeted HMGA1 and HMGA2, miR-603 and miR-326 targeted E2F1. The expression levels of miR-432 were positively correlated with the serum level of prolactin (r = 0.528, p 3

10

2

/

Liang et al. [70]

PREDICTED MIR189

21.7629

10

2

/

Liang et al. [70]

mmu-miR-140

3.0493

10

2

/

Liang et al. [70]

miR-31/506/514/508/509/513

↓ > 10-fold

10

2

/

Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in a normal pituitary glands; Number: the number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article. CDC25A: Cell division cycle 25A.

miR-26a, let-7a, and miR-196a2 was observed to be downregulated, resulting in the increased expression of HMGA1 and HMGA2-specific mRNAs [42], MiRNA-410 was downregulated (0.077fold), whose direct target was CCNB1 (cyclin B1) [63]. MiR-183 was downregulated in aggressive (A, grade 2b) PRL tumors and inhibited the tumor cell proliferation by directly targeting KIAA0101, which was involved in cell cycle activation and inhibition of p53-p21-mediated cell cycle arrest [64]. miRNAs in PRL-secreting pituitary adenomas are summarized in ▶Table 3.

miRNAs in Non-Functioning Pituitary Adenomas In a previous study, miR-107, which targeted AIP, was overexpressed in non-functioning pituitary adenomas and acted as a tumor suppressor [55]. MiR-598, miR-181d, miR-191-3p, and miR181b-5p were significantly upregulated, miR-3676-5p and miR-383 were significantly downregulated, which was suspected to play a significant part in the regulation of tumor suppressor genes in invasive pituitary adenomas [65]. Trivellin observed that some miRNAs (miR-217, miR-216a, miR-215, miR-502, miR-338, miR-10b, miR-96, miR-202, miR-501, miR-18a, miR-450a, and miR-329) were only detected in the NFPA group. MiR-23b, miR-130b [47], miR424 and miR-503 [66] were observed to be downregulated in non-functioning pituitary adenomas compared to that in a normal pituitary gland, while miR-135a, miR-429, miR-140-5p, miR-5823p, miR-582-5p, and miR-938 were upregulated. These miRNAs modulated the TGF-β (transforming growth factor-β) signaling via Smad3 pathway. MiR-197 and miR-33b were found to be overexpressed and decreased the expression of DLK1 (delta like non-canonical Notch ligand 1) [67].


Palmieri et al. [42] noted that a downregulation in let-7a, miR15, miR-16, miR-196a2, and miR-26a led to an increase in the expression of HMGA1 and HMGA2-specific mRNAs. Wang [68] demonstrated a negative correlation between miR-133 and FOXC1 (forkhead box C1). Additionally, the expression levels of miR-424 and miR-503, which directly targeted CDC25A (cell division cycle 25A), were observed to reduce in non-functioning and gonadotrope adenomas, but not in GH-producing tumors. The expression levels of these miRNAs also correlated with pituitary adenoma size [66]. Wei et al. [34] demonstrated that the expression levels of miR-20a, miR-106b and miR-17-5p increased and these miRNAs were involved in pituitary carcinoma metastasis by attenuating target genes PTEN and TIMP2 (TIMP metallopeptidase inhibitor 2). Zheng [69] found that miR-106b was significantly upregulated, affecting the migration and invasion of pituitary adenoma cells by regulating the PTEN/PI3K/AKT signaling pathway and expression of MMP-9. Liang et al. [70] found that when non-functioning pituitary adenomas were compared with normal pituitaries, 25 miRNA genes were upregulated and 15 were downregulated. Among them, 4 miRNAs (miR-124a, miR-10b, miR-523, and miR-146a) were upregulated over 5-fold and 6 miRNAs (miR-31, miR-218, miR-503, miR-506, miR-514, and miR-513) were downregulated more than 10-fold. Butz et al. demonstrated that miR-128a, miR-516a-3p, and miR-155 were overexpressed in the non-functioning pituitary adenomas. These miRNAs decreased Wee1 protein expression and inhibited HeLa cell proliferation [71]. Studies conducted by our research group have found overexpressing miR-524-5p [72] downregulated PTTG1-binding factor (PBF) expression and regulated the biological properties of PDFS(pituitary tumor-derived folliculostellate cell). This could be noted as a potential therapeutic target for non-functioning pituitary adenomas. miRNAs in NF-secreting pituitary adenomas are summarized in ▶Table 4.

187


Expression: ↑: Increase; ↓: Decrease.

Review

▶Table 6 List of microRNAs co-expressed in a variety of pituitary adenomas. miRNA

Co-expression

Fold change

Target genes

Tumor types


miR-26a

↓

/

HMGA1, HMGA2


GH, PRL, NF, FSH, LH


miR-26a

↑

3

PRKCD

Palumbo et al. [38], Mussnich et al. [63], Renjie, Haiqian [57]

miR-16

↓

/

HMGA1, HMGA2

A tumor suppressor

GH, PRL, NF

Amaral et al. [56], Renjie, Haiqian [57]

miR-16

↑

5

/


let-7a

↓

/

HMGA1, HMGA2

Amaral et al. [56]

/

↑

3.3

/

Mussnich et al. [63], Renjie, Haiqian [57]

miR-15

↓

/

HMGA1, HMGA2

Stilling et al. [58], Liang et al. [70]

miR-10b

↑

48.7256 (FSH, LH), 5.75 (NF), 5.686 (ACTH)

/


miR-196a2

↓

/

HMGA1, HMGA2

Mao et al. [35], Butz et al. [66], Liang et al. [70]

miR-503

↓

0.36(GH), > 10fold (NF)

CDC25A (NF, FSH, LH)

GH, NF, FSH, LH

Stilling et al. [58], Liang et al. [70]

miR-514

↓

> 10 (NF, FSH, LH), –27.346 (ACTH)

/

ACTH, NF, FSH, LH

Leone et al. [47]

miR-23b

↓

/

HMGA2

GH, NF

Chen et al. [62]

miR-23b

↑

/

/

PRL


miR-432

↓

/

HMGA2

Chen et al. [62]

miR-432

↑

/

/

PRL


miR-320

↓

/

/

PRL


miR-320

↑

/

/

GH

Palumbo et al. [38]

miR-212

↑

/

GH


miR-212

↓

–3.081

/


miR-493

↓

–4.571

LGALS3, RUNX2 (ACTH)

Chen et al. [62]

miR-493

↑

Mao et al. [35], Palumbo et al. [38]

miR-145

↓

0.42

2

ACTH

ACTH Negatively regulates pituitary cell proliferation

GH, PRL, NF

A tumor suppressor

GH, PRL, NF

ACTH

ACTH, NF, FSH, LH Negatively regulates pituitary cell proliferation


GH, PRL

ACTH Regulates proliferation and apoptosis

LGALS3, RUNX2 (ACTH) IRS-1

GH, PRL, NF

ACTH PRL


GH

Amaral et al. [56]

miR-145

↑

Butz et al. [66]

miR-424

↓

Mao et al. [35], Palumbo et al. [38], Chen et al. [62]

miR-125b

↓

/

IGFBP-3, IGFALS (GH)

Mao et al. [35], Stilling et al. [58]

miR-510

↓

0.47 (GH), –7.476 (ACTH)

/

GH, ACTH

Mao et al. [35], Stilling et al. [58]

miR-542-3p

↓

0.21(GH), –4.837 (ACTH)

/

GH, ACTH

188

ACTH CDC25A

NF, FSH, LH Protein binding, receptor binding, cell communication, and regulation of growth

GH, PRL



Reference

▶Table 6 Continued. List of microRNAs co-expressed in a variety of pituitary adenomas. miRNA

Co-expression

Fold change

Target genes

Tumor types

Trivellin et al. [55], Palumbo et al. [38]

miR-107

↑

2.5 ± 0.39 (GH), 3.5 ± 0.97 (NF)

AIP

Tumor suppressor

GH, NF

Mao et al. [35], Liang et al. [70]

miR-32

↑

5.48 (GH), 3.5503 (NF)

/

GH, NF

Leone et al. [47]

miR-130b

↓

/

CCNA2

GH, NF

Denes et al. [54], Liang et al. [70]

miR-34a

↑

3.4689 (FSH, LH)

AIP(GH)

GH, FSH, LH


miR-34b

↓

/

HMGA1, HMGA2

GH, PRL


miR-603

↓

/

E2F1

GH, PRL


miR-548c-3p

↓

/

HMGA1, HMGA2

GH, PRL


miR-326

↓

/

HMGA2, E2F1


miR-570

↓

/

HMGA2


GH, PRL


miR-633, miR-374b

↓

/

/


GH, PRL

Gentilin et al. [59], Liang et al. [70]

miR-181b

↑

3.2153 (NF)

/

ACTH, NF

Liang et al. [70]

miR-523

↑

6.1540 (FSH, LH), 5.97 (NF)

/

NF, FSH, LH

Liang et al. [70]

miR-520b

↑

3.7698 (FSH, LH), 4.2857 (NF)

/

NF, FSH, LH

Liang et al. [70]

miR-422a

↑

3.7661 (FSH, LH), 3.5085 (NF)

/

NF, FSH, LH

Liang et al. [70]

miR-422b

↑

4.4157 (FSH, LH), 3.835 (NF)

/

NF, FSH, LH

Mao et al. [35], Zhen et al. [72]

miR-524-5p

↓

0.34(GH)

IGFBP-3, IGFALS (GH), PBF (NF)

GH, PRL

Tumor suppressor

GH, NF

Expression: ↑: Increase; ↓: Decrease Fold change: The listed number represents the exact fold change in the expression of miRNAs in tumors when compared to that in normal pituitary glands; Number: The number of pituitary samples, including the number of tumors and normal pituitary glands(as for control); /: Not mentioned in the article HMGA1: High mobility group AT-hook 1; HMGA2: High mobility group AT-hook 2; PRKCD: Protein kinase C delta; CDC25A: Cell division cycle 25A; IGFALS: Insulin-like growth factor binding protein, acid labile subunit; RUNX2: Runt related transcription factor 2; IRS-1: Insulin receptor substrate 1; IGFBP3: Insulin-like growth factor binding protein-3; AIP: Aryl hydrocarbon receptor interacting protein; E2F1: E2F transcription factor 1; PBF: PTTG1 (pituitary tumor-transforming 1) interacting protein

miRNAs in Gonadotropin-Secreting Pituitary Adenomas Butz et al. found that miR-424 and miR-503, which directly targeted CDC25A, were downregulated in gonadotrope adenomas compared to that in a normal pituitary gland [66]. Liang et al. reported that in gonadotropin-secreting pituitary adenomas, 16 miRNA genes were upregulated and 13 were downregulated, six miRNA[miR-422b, miR-10b, miR-222, miR-523, predicted_miR189 and predicted_miR240 (the last two were predicted by a computer program; average of 6.2-fold upregulation)] were upregulated over 4-fold and seven miRNAs [miR-31 (21.5-fold), miR-503, miR-506, Feng Y et al. MicroRNAs in Pituitary Adenomas … Horm Metab Res 2018; 50: 179–192

miR-514, miR-508, miR-509, and miR-513] were all downregulated more than 10-fold. From these listed miRNAs, the most upregulated gene was miR-10b and the most downregulated gene was miR-503 (39.8-fold) [70]. miRNAs in gonadotropin-secreting pituitary adenomas are summarized in ▶Table 5.

miRNAs Co-Expressed in a Variety of Pituitary Adenomas Several miRNAs have been reported to be co-expressed in a variety of pituitary adenomas. These co-expressed miRNAs are listed in

189


Reference

Review

miRNAs Differently Expressed in a Variety of Pituitary Adenomas The expression levels of miRNA-16, let-7a, and miRNA-26a decreased in GH, PRL, NF, FSH and LH pituitary adenomas, whereas they increased in ACTH, FSH, LH pituitary adenomas. The fold changes were observed as 5, 3.3, and 3, respectively. The reason that leads to the opposite expression in ACTH, FSH, LH pituitary adenomas needs to be determined. MiR-26a targeted HMGA1 and HMGA2 in GH, PRL, NF, FSH, LH pituitary adenomas, whereas the target gene in ACTH was PRKCD. Here, the relationship between the target gene and the tumor types would be an interesting phenomenon. It is also necessary to determine if different types of tumors transduce different pathways. Further studies are required to determine if PRKCD, HMGA1, and HMGA2 are all target genes of miR-26a. Likewise, it was also observed that miR-23b, miR-320, miR-212, miR-432, miR-145 and miR-493 had an opposite expression in different types of tumor, Xu, Y., et al. found that the expression of CUL4A was high in NF adenomas and low in ACTH adenomas [73], Righi et al. suggested that a slightly higher level of IMP3 expression in PRL-GH-TSH adenomas(derived from pit-1-dependent lineages) than other subtypes of pituitary adenomas [74], Chile et al. showed that CRABP1, RERG mRNA was significantly upregulated and GRP mRNA was down-regulated in NFPA, whereas the CRABP1 mRNA was down-regulated in PRL-secreting adenomas; the RERG mRNA was only highly expressed in ACTH-secreting adenomas and low expression in other functioning adenomas [75]. Further studies are needed to elucidate this phenomenon. Comparing different types of pituitary adenomas with normal pituitary glands, more and more miRNAs are found aberrant expressed; the research of miRNA variation and expression in pituitary adenoma has proved to be crucial in exploring tumorigenesis. Currently, the clinical use of miRNA-based therapies for tumor is rapidly advancing, and miRNAs could be used as the estimation of outcome and modification of response in anti-tumor treatment including resistance to chemo- and radiotherapy [76], for example, alterations in miRNA expression profiles could act as ‘response prediction’, providing information about sensitivity or resistance of certain tumor types to different treatments before starting therapy; the modification to miRNA's expression may possibly enhance sensitivity to the applied chemo- or radiotherapy (‘response modulation’). In fact, Teo et al. demonstrated that a single-nucleotide polymorphism (SNP) located within a miRNA-binding site could alter mRNA translation, influence cancer risk and radiotherapy outcomes [77].

190

We have reviewed the effects of aberrant miRNA expression in human pituitary adenomas and summarized some corresponding target genes, biological significance compared to normal pituitary gland, which has uncovered a number of candidate miRNAs and target genes that were thought to contribute to tumorigenesis, recurrence, hormonal hypersecretion and treatment. Despite the limitations present in the both individual studies and the review itself, it represents a strong foundation from where deeper investigations can begin.

Funding Information This research was supported by Science and Technology Planning Projec t of Guangdong Province (No.2016A050502024, No.2017A050501011), The National Nature and Science Grant of China (No.81773943), and Sun Yat-Sen University Clinical Research 5010 Program (No.2016008).

Conflict of Interest The authors declare that they have no conflict of interest.

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▶ Table 6. MiR-26a was found in 5 types of pituitary adenomas, namely GH-secreting pituitary adenomas, ACTH-secreting pituitary adenomas, prolactinomas, non-functioning pituitary adenomas, and gonadotrope adenomas; miR-16 and let-7a were found in 4 different types of pituitary tumors; 7 miRNAs(miR-15, miR-23b, miR-514, miR-10b, miR-196a2, miR-503, miR-424) were found in 3 different types of tumors; and the remaining miRNAs were upregulated or downregulated in at least 2 different types of tumors.

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Notice This article was changed according to the erratum on March 7th 2018. Erratum Fig. 1 was incomplete in the print version and in the PDF of the e-first version. In the e-first version the second author should have been marked with an * (the authors Yajuan Feng and Zhi-gang Mao contributed equally to this work).



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