Emerging role of microRNAs in cancer stem cells: Implications in cancer therapy

Table 1 Some of the potential microRNAs involved in regulation of cancer stem cells

MicroRNAs	Transcript target	Relevance to cancer progression and its biological functions	Ref.
Upregulated microRNAs
miR-1246	CCNG2	Pancreatic cancer: Induces chemoresistance and CSC-like properties	[53]
miR-495	E-cadherin and REDD1	Breast cancer: Promotes oncogenesis and hypoxia resistance	[54]
miR-371-373 cluster	Wnt/β-catenin, DKK1	Many cancers: Promotes cell growth and invasive activity	[55,56]
	Myc	Liver cancer: Regulates the properties of CSCs
miR-216a/217	PTEN and SMAD7	Hepatocellular carcinoma: Increased proliferation, migration and metastatic ability	[57]
miR-210	Nanog, Oct4 and EZH2	Pancreatic cancer: Increased cell migration and invasion	[58]
miR-191	BASP1, Wnt/β-catenin	Lung cancer: Increased migratory potential and neoplastic properties	[59]
miR-130b	P53-induced nuclear protein 1	Acute myeloid leukemia: Regulates hematopoietic stem cells	[60]
miR-29a	P53-induced nuclear protein 1	Acute myeloid leukemia: Regulates hematopoietic stem cells	[61]
miR-21	Nanog, Oct4 and EZH2	Pancreatic cancer: Increased cell migration and invasion	[58]
miR-18	DLL4, inhibitor of Notch signaling	Glioma: Promotes tumorigenic potential of GSCs	[62]
Downregulated microRNAs
Let-7	Lin-28	Colon adenocarcinomas: Promotes cell migration, invasion and transforms immortalized colonic epithelial cells	[24,63]
		Pancreatic cancer: Increased pluripotency
miR-487b	SUZ12, BMI1, WNT5A, MYC, and KRAS	Lung cancer: Increased proliferation and invasion	[64]
miR-451	SMAD 3 and 4	GBM: Controls GBM stem cells differentiation	[41]
miR-326	Hh smoothened signal transducer	Chronic myeloid leukemia: Increased cell proliferation and decreased apoptosis	[65]
miR-204	Sox4 and Ephrin receptor EphB2	Glioma: Involved in GSCs self-renewal and invasion	[66]
miR-200 family	VEGFR1, VEGFR2 and EMT-related transcription factors	Pancreatic cancer: Regulates CSCs properties	[63]
miR-200a	ZEB1, ZEB2, SNAIL and SLUG N-cadherin, ZEB1,vimentin,	Pancreatic cancer: Increased cell migration and invasion	[67]
	E-cadherin
miR-181	ATM	Breast cancer: Regulates the properties of CSCs	[68]
miR-150	MYb	Acute myeloid leukemia: Blocking of myeloid differentiation	[69]
miR-143/145 cluster	KRAS2 and its downstream effector RREB1	Pancreatic cancer: Regulates CSCs survival	[70]
miR-145	Oct4, Sox2, Nanog, Klf4 as well as Kras and Rreb1	Pancreatic cancer: Increased pluripotency	[63]
miR-128	Histone methylation [H3K27me(3)], Akt phosphorylation, p21(CIP1) Bmi-1	Glioma: Increased self-renewal and proliferation	[71]
miR-107	Nanog, Oct3/4, and Sox2	Head and neck squamous cell carcinoma: Increased CSC proliferation	[72]
miR-100/let-7a-2/miR-125b-1 cluster	Myc	Liver cancer: Regulates the properties of CSCs	[56]
miR-34 family	Notch and Bcl-2	Pancreatic cancer: Involved in self-renewal of CSCs	[28,29]
miR-29b-1	CD133, N-Myc, CCND2, E2F1 and E2F2, Bcl-2, IAP-2, Oct3/4, Sox2 and Nanog	Osteosarcoma: Increased proliferation, self-renewal and chemoresistance	[73]
miR-27a	14-3-3theta;, Bax and Bad	Acute leukemia: Regulate apoptosis	[74]
miR-23b	Cell cycle arrest	Glioma: Inhibits proliferation	[75]

CCNG2: Cyclin-G2; DKK1: Dickkopf-1; PTEN: Phosphatase and tensin homolog; BASP 1: Brain abundant, membrane attached signal protein 1; ATM: Ataxia telangiectasia mutated; Myb: Myeloblastosis protooncogene protein; RREB1: Ras-responsive element binding protein-1; IAP-2: Inhibitor of apoptosis 2; CCND2: Cyclin D2; GSC: Glioma stem cell; CSC: Cancer stem cell; REDD1: Regulated in development and DNA damage responses 1; Myc: Myelocytomatosis viral oncogene; SMAD7: Homologs of caenorhabditis elegans protein small body size and drosophila protein mothers against decapentaplegic family member 7; Oct 4: Octamer-binding transcription factor 4; EZH2: Enhancer of zeste homolog 2; P53: Tumor protein 53; DLL4: Delta like ligand 4; SUZ12: Polycomb repressive complex 2 subunit; BMI1/Bmi-1: BMI1 proto-oncogene, polycomb ring finger; WNT 5A: Wingless-type MMTV integration site family, member 5A; KRAS: Kirsten rat sarcoma viral oncogene homolog; SMAD3 and 4: Homologs of caenorhabditis elegans protein small body size and drosophila protein mothers against decapentaplegic family member 3 and 4; Hh: Hedgehog; Sox 4: Sex-determining region Y-box containing gene 4; EphB2: Ephrin type-B receptor 2; VEGFR1: Vascular endothelial growth factor receptor 1; VEGFR2: Vascular endothelial growth factor receptor 2; EMT: Epithelial-to-mesenchymal transition; ZEB1: Zinc finger e-box binding homeobox 1; ZEB2: Zinc finger e-box binding homeobox 2; E-cadherin: Epithelial-cadherin; Klf4: Kruppel like factor 4; H3K27 me (3): Histone H3K27me3 (trimethy Lys27); Akt: Protein kinase B; Bcl-2: B-cell lymphoma 2; E2F1: E2F transcription factor 1; E2F2: E2F transcription factor 2; Bad: Bcl-2-associated death promoter; Bax: Bcl-2-associated X protein; P21 (CIP1): Cyclin-dependent kinase inhibitor 1A; GBM: Glioblastoma multiforme.

Table 2 Targeting cancer stem cells with specific microRNAs as a potential combinational therapeutic strategy in human cancer

Co-delivery of microRNAs/anti-cancer drug	Biological functions	Cancer type	Ref.
Oncogenic microRNAs
miR-9/temozolomide	Inhibit the expression of drug efflux transporter, P-glycoprotein	Glioblastoma multiforme	[39]
miR-21/metformin, 5-Fluorouracil and Oxaliplatin	Target Wnt/β-catenin	Colon cancer	[38]
miR-125b/temozolomide	Target PIAS3, which contributes to reduced STAT3 transcriptional activity and subsequent decreased expression of MMP-2 and -9	Glioblastoma	[40]
miR-125b/temozolomide	Target pro-apoptotic Bcl-2 antagonist killer 1 and sensitize CSCs to temozolomide induced apoptosis	Glioblastoma	[76]
Tumor suppressor microRNAs
miR-612/cisplatin, 5-Fluorouracil	Target Wnt/β-catenin, regulate EMT and inhibit cell proliferation, migration, invasion, and metastasis	Liver cancer	[48]
miR-205/gemcitabine	Decreased tumor cell population and increased apoptosis	Pancreatic cancer	[42]
miR-200c/docetaxel	Reduced TUBB3 level, and reversed EMT	Gastric cancer	[43]
miR-146a/cetuximab	Target Numb to stabilize β-catenin, regulate EMT, direct ACD-to-SCD switch	Colorectal cancer	[77]
miR-145/metformin, 5-Fluorouracil and Oxaliplatin	Target Wnt/β-catenin	Colon cancer	[38]
miR-34 family/5-Fluorouracil	Repression of c-Kit by p53	Colorectal cancer	[45]
miR-34a/doxorubicin	Target Notch1 and reduce cancer stem cell properties	Breast cancer	[44]

STAT: Signal transducer and activator of transcription; PIAS3: Protein inhibitor of activated STAT; MMP: Matrix metalloproteinase; ACD: Asymmetrical cell division; SCD: Symmetrical cell division; EMT: Epitheilal-to-mesencymal transition; CSC: Cancer stem cell; MMP: Matrix metalloproteinase; TUBB3: Tubulin beta class III.