Table 5.

Varying functions of microRNAs in pituitary tumorigenesis with illustrative examples from publications from the last 5 years.

Major Function	Mechanisms of Action and/or Relevant Examples	Supporting Evidence
MicroRNAs can demonstrate a tumor suppressor action by targeting oncogenic gene products for degradation	MicroRNAs regulate the cell cycle, facilitating increased proliferation when deregulated (230).	miR-23b and miR-130b, targeting HMGA2 and cyclin A2 respectively, are downregulated in GH-PTs, GT-PTs and NFPTs (233). HMGA2 is a high mobility group protein, which shows increased expression in pituitary tumors (234, 235). HMGA2 overexpression enhances E2F1 activity and drives cell cycle (236, 237) microRNAs targeting HMGA2 and E2F1 are downregulated in pituitary tumors (235, 238).
		miR-410 targeting the cyclin B1 gene is downregulated in GT-PTs (239).
		miR-186 targets SKP2, which inhibits expression of p27, a negative regulator of G1 cell cycle progression, increasing proliferation. In human pituitary tumors, miR-186 and p27 expression is downregulated, while SKP2 expression is upregulated (240). In vitro, SKP2 overexpression decreases p27 expression and increases cell growth (240).
	Multiple microRNAs, when down regulated, lead to increased expression of PTTG1 and its partners.	p53 activates transcription of miR-329, miR-300, miR-381, and miR-655 in pituitary tumor cells, which target PTTG1 (241).
		miR-423-5p (targeting PTTG1) shows decreased expression in GH-PTs with increased PTTG1 expression compared to normal pituitary (242).
		Overexpression of miR-524-5p downregulates expression of PTTG1 binding factor, which interacts with PTTG1 to mediate downstream effects (243) and significantly attenuates proliferation, migration, and invasion in folliculostellate cells (244); downregulation of this microRNA may mediate increased proliferation in the pituitary through PTTG1.
	Other tumor-suppressive microRNAs which show reduced expression in human pituitary tumors or relevant cell lines.	miR-205-5p targeting CBX1 in pituitary cell lines (245).
		miR‑1 targeting G6PD in human pituitary tumors (246).
		miR-34a targeting SOX7 in GH4C1 cells (247).
		miR-378 targeting RNF31 in human pituitary tumors (248).
Increased expression of certain microRNAs can drive tumorigenesis by targeting gene products with tumor suppressor roles for degradation.	High levels of miR-107 (249) and miR-34 (250) target AIP mRNA in pituitary tumors.	miR-107 expression is significantly upregulated in GH-secreting and nonfunctioning pituitary tumors and inhibits in vitro AIP expression (249)
		miR-34 is highly expressed in tumors with low AIP protein levels compared to tumors with high levels (250). miR-34 overexpression in HEK293 and GH3 cells inhibits endogenous AIP expression (250).
MicroRNAs may regulate subtype-specific mechanisms of tumorigenesis.	Distinct profiles identified in tumor subtypes with differential microRNA expression specific to subtype.	Next generation sequencing and other techniques in GH-PTs, GT-PTs and NFPT subtypes (251, 252).
		TSP-1, which has a tumor suppressor role, shows decreased expression in ACTH-PTs with increased miR-449c expression inhibiting its expression (253).
		Four groups, miR1 to miR4, are strongly associated with tumor type with PIT1-lineage tumors being distinctly different from GT-PTs and ACTH-PTs (17).
MicroRNAs play a prominent role in driving tumor invasion.	Decreased expression of mi-RNAs can have an anti-apoptotic effect, mediating invasion:	Downregulation of miR-132 and miR-15a/16 with upregulation of SOX5 is seen in invasive tumors (254). MiR-15a and miR-16-1 are also downregulated in pituitary tumors that develop after 12 months of age in mice with heterozygous Men1 knockout (255). MiR-16 expression, which induces apoptosis (via Bax) and decreases proliferation, is reduced in pituitary tumors (256).
		Invasive pituitary tumors show lower miR-21 expression with increased expression of its target, PITX2, which has an antiapoptotic role (257).
		MiR-145-5p expression (targeting TPT1) correlates negatively with NFPT invasiveness. MiR-145-5p brings about apoptosis through Bcl-xL downregulation and Bax upregulation (258).
		MiR-543 expression is increased in invasive tumors (259) and activates the Wnt/ β-catenin pathway by downregulating Smad7. Overexpression of miR-543 in HP75 cells increases cell proliferation, migration and invasion and decreases apoptosis (259).
	microRNAs driving invasion specific to tumor subtype have also been identified:	MiR-183, which targets KIAA0101 (a cell cycle activator), is downregulated in aggressive PRL-PTs and demonstrates an inverse correlation with Ki-67 indices (260).
		MicroRNA 106b~25 cluster shows increased expression in invasive ACTH-PTs and Crooke cell adenomas (261). MiR-106b is upregulated in pituitary tumors and can increase migration and invasion of pituitary tumor cells through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (262, 263).
		Differential microRNA profiles have been identified in invasive NFPTs (264).
		MiR-26b (targeting PTEN) is upregulated and miR-128 (targeting BMI1) is down-regulated in GH-PTs compared to control and is shown to mediate growth and invasiveness of pituitary tumor cells (265). MiR-338-3p expression is increased in invasive GH-PTs and is mediated through upregulation of PTTG1 (266).
		The same microRNAs may even play different roles in different tumor subtypes: miR-410-3p significantly upregulates proliferation, invasiveness, cyclin B1 levels and activation of MAPK, PTEN/AKT, and STAT3 signaling pathways in gonadotroph and corticotroph cells but not in somatotroph cells (267).
	Other microRNAs discovered recently through comparison of invasive and noninvasive pituitary tumors (target gene in parentheses):	Reduced expression of microRNA in invasive tumors:
		microRNA	Targeted gene	Reference
		miR-145	FSCN1	(268)
		miR-124	PTTG1IP	(268)
		miR-183	EZR	(268)
		miR-148-3p and miR-152	ALCAM	(269)
		miR-200b	PKCα	(270)
		miRNA-145	AKT3	(271)
		Increased expression of microRNA in invasive tumors:
		miR-26a	PLAG1	(272)
		miR-20a and miR-17-5p	PTEN and TIMP2	(273)