Table 2.

Aberrantly expressed miRNA in MCL.

Type of ncRNA	ncRNA	Expression in MCL	Target	Mechanism/Target/Pathway	References
miRNA	miR-17-92 cluster (miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1, miR-92-1)	Upregulated	PTEN/PHLPP2/BIM	A mouse model demonstrated that c-Myc can both activate the expression of the miR-17-92 gene cluster and be regulated by it, suggesting negative regulation between c-Myc and the miR-17-92 gene cluster. Loss of regulation control of this cluster is involved in the development of B-cell non-Hodgkin lymphoma (B-NHL). MiR-17-92 can also inhibit phosphatase and tensin homolog (PTEN), PHLPP2, P21 and Bcl-2-like 11 (Bim) expression, promoting proliferation and suppressing cancer cell apoptosis. High expression levels of the miR-17-92 cluster are also related to poor survival rate in patients with MCL.	[30,96,97,98,99,100,101]
miRNA	miR-15a/16-1	Loss/ downregulated	BMI1	MiR-15a/16-1 inhibits cell proliferation, promotes apoptosis of cancer cells and suppresses tumorigenicity by targeting multiple oncogenes associated with short overall survival. MiR-15a/16-1 targets the proto-oncogene Bmi1, which directly regulates pro-apoptotic genes such as Bim and PMAIP1. MiR-15a/16-1 downregulation enhanced the anti-apoptotic potential of MCL.	[102,103,104,105,106,107,108,109,110,111,112]
miRNA	miR-34a	Downregulated	MYC/CDK4/6/CCND1/FOXP1/BCL2	MCL patients with downregulated miR-34a had short overall survival associated with poor prognosis. Low expression of miR-34a was associated with high expression of MYC oncogene, which was co-regulated with CDK4/6 and CCND1 to further promote cell-cycle progression and the development of MCL. MiR-34a is involved in the regulation of the tumor suppressor gene TP53 via FOXP1 and BCL2, thus affecting the differentiation and apoptosis of B cells.	[113,114,115,116,117]
miRNA	miR-29a/b/c	Downregulated	CDK6/RB1	MiR-29 family members are critical regulators of extracellular matrix (ECM) proteins and signaling pathways associated with fibrosis via targeting of collagens, fibrillins, and elastin. MiR-29 inhibition activated CDK4/CDK6 and RB1 in MCL. Low expression of miR-29 was associated with poor prognosis in MCL.	[104,118,119,120]
miRNA	miR-150	Downregulated	MET/FOXP1	MiR-150 inhibits the proliferation and promotes the apoptosis of MCL cells by negatively regulating MET and FOXP1 expression. Premature miR-150 expression severely impairs B-cell development due to a pro- to pre-B-cell transition block, whereas miR-150 deletion promotes B1-cell expansion and increases antibody production. HGF/MET and FOXP1 signaling pathways are considered as treatment targets for B-cell lymphoma, particularly in MCL.	[121,122]
miRNA	miR-18b	Upregulated	unknown	MiR-18b decreases the MCL cell line proliferation rate without inducing apoptosis, suggesting that it may render MCL cells resistant to chemotherapy by decelerating the cell proliferation. MiR-18b is associated with poor prognosis.	[123,124]
miRNA	miR-20b	Upregulated	unknown	MiR-20b plays a role in survival of patients with MCL. High expression levels of miR-20b are associated with a worse prognosis.	[97,121,125,126]
miRNA	miR-223	Downregulated	SOX11	MiR-223 expression is repressed in MCL. It inhibits cell proliferation and promotes G0/G1 accumulation and cell apoptosis. Low expression of miR-223 predicts poorer outcomes in MCL, probably due to its direct targeting of SOX11.	[50,127,128,129,130]
miRNA	miR-101	Downregulated	EZH2	Inhibits cell proliferation and induces cell apoptosis of MCL by targeting EZH2. Low miR-101 expression is associated with low overall survival rates.	[131]
miRNA	miR-100	Downregulated	mTOR	Inhibits cell proliferation in MCL by targeting mTOR.	[132]
miRNA	miR-155-3p	Downregulated	LT-β/non-canonical NF-κB signaling	Overexpression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties.	[134,135,136,137]
miRNA	miR-129-2	Downregulated	SOX4	MiR-129-2 has been shown to be a tumor suppressor hypermethylated in epithelial cancers. MiR-129 overexpression inhibited cellular proliferation and enhanced cell death, with concomitant SOX4 mRNA downregulation.	[136]
miRNA	miR-26-A-1	Downregulated	EZH2	MiR-26-A-1 is a tumor suppressor. Epigenetic silencing of miR-26-A-1 leads to increased EZH2 levels, which, in turn, translate into a worse outcome.	[138]
miRNA	miR-342-3p	Downregulated	Co-regulated with its host gene, EVL	MiR-342-3p is a tumor suppressor co-regulated with its host gene, EVL, by promoter DNA methylation in B-cell lymphomas including MCL. Re-expression of miR-342-3p and EVL and the tumor suppressor function of miR-342-3p were demonstrated by the inhibition of cellular proliferation and increase of cell death.	[139]
miRNA	miR-92b/96	Downregulated	PRMT5	Low expression of miR-92b and miR-96 is associated with enhanced PRMT5 translation which is overexpressed in aggressive B-cell NHL, including MCL. Re-expression of miR-92b and miR-96 inhibits PRMT5 translation and alters the growth of MCL cells.	[140,141]
lncRNA	MALAT1	Upregulated		MALAT1 is associated with cancer progression, acts through repression of TP53 promoter and increases EZH2 translation. EZH2, in turn, binds a ROR1-AS1 lncRNA, which leads to increased cell proliferation in MCL cell lines.	[164]
lncRNA	ROR1-AS1	Upregulated	SOX11/P16	Overexpression of ROR1-AS1 lncRNA promoted growth of MCL cells and resistance to ibrutinib (BTK inhibitor) and dexamethasone treatment through regulation of SOX11 and P16 expression.	[162]
lncRNA	FAS-AS1	Upregulated		The promoter region of FAS-AS1 is regulated by EZH2, which is upregulated in MCL. FAS-AS1 modulates alternative splicing of the FAS gene, a central inhibition molecule in the extrinsic apoptosis pathway, thereby downregulating FAS.	[7,165]
lncRNA	SNHG4	Upregulated	Co-regulated with eIF4	SNHG4 plays a role in the regulation of gene expression and can bind with eIF4E and regulate protein translation in MCL. Knockdown SNHG4 expression through siRNA inhibits cell proliferation and global protein translation.	[167]
lncRNA	SNHG12, FTX, SNHG5, ZNFX1-AS1	Upregulated	Associated with translation machinery via eIF4E/modulation of c-Myc translation	These lncRNAs are associated with translation machinery via eIF4E-RNA-binding motifs in MCL tumor cells. SNHG5 and SNHG12 can also modulate c-Myc translation in MCL cells.	[168]
lncRNA	GAS5	Downregulated	eIF4E	Downregulation of the tumor suppressor GAS5, which interacts with translation initiation factor eIF4E to suppress the translation of c-MYC mRNA, resulted in decreased apoptosis levels in MCL cell lines. Overexpression of GAS5 constructs is also sufficient to induce growth arrest in normal and transformed human lymphocytes.	[169]
lncRNA	GATA6-AS	Downregulated	GLUT1	GATA6-AS is involved in endothelial–mesenchymal transition. Overexpression of lncRNA GATA6-AS inhibits cancer cell proliferation by downregulating GLUT1 and therefore inhibits glucose uptake in MCL.	[170]
lncRNA	LINK-A	Upregulated	Survivin (not directly)	LINK-A lncRNA overexpression promotes cell proliferation, inhibits cell apoptosis and upregulates survivin expression.	[171]
circRNA	circCDYL	Upregulated	miR-101	Overexpression of circCDYL in MCL cells promotes malignant proliferation, self-renewal and chemoresistance. Inhibition of circCDYL suppressed cell proliferation in vitro, consistent with its functions in regulating transcription, programmed cell death, cell death and apoptosis. CircCDYL might serve as a sponge for miR-101, targeting EZH2 and further regulating p21 and p27.	[183]
circRNA	circ_cgga162	Upregulated	unknown	High circ_cgga162 expression was associated with low overall survival rate.	[184]
circRNA	circRAB11FIP1	Downregulated	unknown	Low circRAB11FIP1 expression was significantly associated with TP53 mutations and with shorter median time to progression.	[180]