MicroRNAs in colorectal cancer: Role in metastasis and clinical perspectives

Table 1 MicroRNAs involved in angiogenesis

MicroRNAs	Target genes/activators	Effect on angeogenesis	Ref.
miR-194	THBS1	↑ Enhance	[69]
miR-221, miR-222	c-Kit, Stat5A, ENOS, and ETS1	↓ Inhibit	[70]
miR-17-92 (Oncomir-1)	TSP-1 and CTGF	↑ Enhance	[71]
miR-126	SPRED1 and PIK3R2 p85beta	↑ Enhance	[72]
miR-210	Hypoxia-induced miR-210 activation accompanied by KRAS mutation	↑ Enhance	[73]
miR-497	IGF1-R	↓ Inhibit	[74]
miR-424	Hypoxia-induced activation of angiogenic genes	↑ Enhance	[75]

ENOS: Endothelial nitric oxide synthase; ETS1: V-ets erythroblastosis virus E26 oncogene homolog 1; Stat5A: Signal transducer and activator of transcription 5A; CTGF: Connective tissue growth factor; TSP-1: Encodes thrombospondin-1; SPRED1: Sprouty-related protein1; PIK3R2: Phosphatidylinositol-3-kinase regulatory subunit; KRAS: V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; IGF1-R: Nsulin-like growth factor 1 receptor gene.

Table 2 MicroRNAs and invasion

MicroRNAs	Dysregulation	Remarks	Ref.
miR-31	↑	Contributed to the invasive nature of CRC cells in vitro and in vivo	[76]
miR-122	↑	Non-neoplastic tissue to dysplasia	[77]
	↓	Dysplasia to inflammatory bowel disease-associated CRC	[77]
miR-200 family	↑	Associated with acquiring an aggressive phenotype	[78]
miR-328	↓	Accompanied by a high fraction of side population (SP) cells showing cancer stem like properties	[79]
miR-143	↓	Stimulated cell growth, migration and invasion	[80]
miR-145, miR-103 and miR-107	↑	Promoted local invasion and liver metastasis in a mouse model	[81]
miR-29a	↑	Elevated in CRC tumor samples compared to normal epithelial tissue; a specific and sensitive marker discriminating CRC with liver metastases from non-metastatic CRC	[82,83]
miR-21, miR-17, miR-19a	↑	Favored cell proliferation and CRC metastasis	[84]

CRC: Colorectal cancer; miRNA: MicroRNA.

Table 3 Intravasation, extravasation and colonization

MicroRNAs	Dysregulation	Effect	Ref.
	Intravasation and extravasation
miR-21	↓Pdcd4	↑ Intravasation and metastatic potential	[34,85]
miR-126	↓VCAM-1	↓ Decreased cell-cell adhesion, leukocytes-epithelial cell adherence, inflammation	[86]
miR-155		Required for adaptive and innate immunity	[40]
miR-17-92		Adaptive differentiation of B cells and conventional T cells	[40]
	Colonization
miR-328	↓ in SP cells	Low miR-328 expression correlated with high SP fraction	[79]
miR-26b	↓ HUES-17 and CRC cell line	↓ Cell growth and induction of apoptosis	[87]
miR-103/107	↓DAPK and KLF4	↑ Colonization	[69]

Table 4 MicroRNAs as diagnostic markers

MicroRNAs	Sensitivity	Specificity	Remarks	Ref.
	Plasma
miR-29a	69%	89.1%	Upregulated in CRC plasma, associated with advanced TNM stages	[82]
miR-92a	64%	70%	Upregulated in CRC plasma; could distinguish CRC from other GI cancers and IBD; not associated with TNM stages	[50]
miR-17-3p	89%	70%	Upregulated in CRC plasma	[51]
miR-92a	84%	71.2%	Upregulated in CRC plasma; not associated with TNM stages	[82]
	Fecal
miR-17-92 cluster	69.5%	81.5%	Upregulated in stool of CRC patients	[88]
miR-135	46.2%	95%	Upregulated in stool of CRC patients	[88]
miR-92a	50%	80%	Upregulated in stool of CRC patients	[89]
miR-21	50%	83%	Upregulated in stool of CRC patients	[89]

CRC: Colorectal cancer; miRNA: MicroRNA; TNM: Tumour-node-metastasis.

Table 5 MicroRNAs as therapeutic, potential prognostic and predictive markers for colorectal cancer

MicroRNAs	Dysregulation	Clinical phenotypes	Ref.
miR-221	Upregulated in CRC	Prognostic factors for poor overall survival in CRC patients	[90]
miR-141	Upregulated in CRC	Higher level associated with poor survival; an independent prognostic factor for advanced CRC	[71]
pre-miR-423	Upregulated in CRC	SNPs in these miRNAs were significantly associated with recurrence-free survival in CRC	[91]
pre-miR-608	Upregulated in CRC		[91]
miR-222	Upregulated in CRC	Played a role in the development of MDR by modulation of ADAM-17 in CRC	[79,92]
miR-328	Upregulated in CRC	Chemotherapeutic insensitive CRC cells, carrying stem cell-like properties, could be reversed by restoring miR-328 to normal	[79]
let-7g	Upregulated in CRC	Higher level associated with poor S-1 response; was prognostic in early-stage CRC	[10,93]
miR-18a	Upregulated in CRC	Higher level associated with poor overall survival	[94]
miR-21	Upregulated in adenoma, CRC, and liver metastases	Higher level associated with lymph node metastasis, poor survival, poor therapeutic outcomes, rapid recurrence, and shorter disease-free interval	[88]
miR-31	Upregulated in CRC	Higher level associated with higher TNM stages and local invasion	[91]
miR-106a	Upregulated in colon cancer	Higher level associated with longer disease-free survival and overall survival	[10]
miR-143	Downregulated in colon cancer and liver metastases	Lower level associated with larger tumour size and longer disease-free interval; expression levels served as an independent prognostic biomarker for KRAS wild-type CRC	[65,91]
miR-145	Downregulated in CRC	Lower level associated with large tumour size and tumour location	[65,91]
miR-181b	Upregulated in CRC	Higher level associated with poor S-1 response	[10]
miR-320	Downregulated in MSS tumour	Lower level associated with shorter progression-free survival	[94]
miR-498	Downregulated in MSS tumour	Lower level associated with shorter progression-free survival	[94]

Up- or downregulation is stated as miRNA expression relative to normal colon tissue, or MSS relative to MS. CRC: Colorectal cancer; miRNA: MicroRNA; MSS: Microsatellite stable tumour; TNM: Tumour-node-metastasis.