Table 1 Interaction between ncRNAs and Shh signaling based on cell line studies

Alopecia

XIST, miR-424

3D-cultivated DP cells

↑↑ XIST: ↑ DP mediated hair follicle regeneration via targeting miR-424 to increase Shh expression

[16]

Breast cancer

miR-26a, FAM98A, SHH, SMO and GLI1

SK-BR-3, BT474, MDA-MB-231, MDA-MB-468, MCF-7, and MCF-10A

↑↑ miR-26a: ↓ proliferation, clone formation and metastasis, but ↑ sensitivity cells to docetaxel via targeting FAM98A, and reducing SHH, SMO and GLI1 expression levels

[20]

LOC101930370, miR-1471, and Gli-1

MCF-7, MDA-MB-231, BT-474, SKBR3

∆ LOC101930370: ↓ cells progression via increasing miR-1471 and inhibiting SHH and Gli-1 expression

[21]

lncRNA-Hh, Twist, Shh-GLI1 signaling, SOX and OCT4

MCF‐7, Hs578T, BT549, MDA‐MB‐231, human mammary epithelial cell line MCF10A

∆ lncRNA-Hh: ↓ the activity of Shh-GLI1 signaling

[22]

Breast cancer brain metastasis

circBCBM1, miR-125a/BRD4 axis, MMP9

231-BR cells

↑↑ circBCBM1: ↑ breast cancer brain metastasis via regulating miR-125a/BRD4 axis

[23]

Cardiopoesis

miR-210

embryonic stem cells

↑↑ SRF-dependent miR-210 expression: ↓ Shh signaling pathway activity via targeting of Shh, thus ↓ proliferation and cardiomyocyte progenitor differentiation

[17]

Cervical cancer

miR-129-5p, ZIC2

C-33A cell line and Hela

↑↑ miR-129-5p: ↓ invasion, migration and tumor angiogenesis via targeting ZIC2 and downregulating the Hedgehog signaling pathway

[28]

Congenital diaphragmatic hernia

miR-130a-5p, Foxa2

lung explant culture, HEK293T and BEAS-2B cells

∆ miR-130a-5p: ↓ CDH-associated abnormal branching morphogenesis

↑↑ miR-130a-5p: ↓ differentiation and ↑ apoptosis via targeting Foxa2 and in turn ↓ activation SHH signaling pathway

[18]

Craniofacial development

miR-199b, HIF1A, MAP3K4

chicken embryonic fibroblasts (DF-1 cells)

↑↑ miR-199b: ↓ SHH expression in the FEZ and craniofacial malformations via targeting HIF1A and MAP3K4

[19]

Diabetic foot ulcer

miR-155/ PTCH1 axis

EPCs

High glucose condition: ↑ miR-155

↑↑ miR-155: ↑ impaired EPCs function by targeting PTCH1 (a receptor of shh signaling pathway)

[29]

Embryonal tumors

LIN28A, let-7, Wnt and Shh signaling

ETMRs

↑↑ LIN28A: ↓ maturation of let-7 microRNAs, thus modulating Wnt and Shh signaling

let-7a-miRNA could target Gli1, Gli2, and Gli3 mRNAs

Wnt and Shh signaling pathways are able to induce ETMR-like tumors

[30]

Embryonic cardiac malfunctions

miR-30c, Gli2 and Ptch1 (Shh signaling pathway)

P19 cells

↑↑ miR-30c ↑ proliferation by promoting cell entry into S phase but also ↓ apoptosis, and ↓ dimethyl sulfoxide-induced differentiation of P19 cells via targeting Gli2 and Ptch1, thus inhibiting the Shh signaling pathway

[31]

Embryonic lung development

miR-326, Arrestin β1

embryonic lung mesenchymal cells

Levels of miR-326 and its host gene, Arrestin β1, are increased in embryonic lung mesenchymal cells and Shh activity influences it

miR-326: ↓ Shh signaling via directly targeting Smo and Gli2

[32]

Gallbladder carcinoma

SNHG6/miR-26b-5p axis

GBC-SD and NOZ

∆ SNHG6: ↑ cell apoptosis, ↓ growth, and ETM via upregulation of miR-26b-5p, thus inhibiting Gli1, Gli2, Shh, Smo, N-cadherin, vimentin and Snail, and promoting Gli3 and E-Cadherin expression

[33]

Glioblastoma Multiforme

miR-9, PTCH1, Gli 1

U87, T98G, HEK293, CCL64, BT145 and BT164

↑↑ miR-9: ↓ PTCH1 (via a SHH-independent method for TMZ resistance) and ↑ Gli 1 levels, thus activating the SHH pathway and also ↑ drug efflux transporters, MDR1 and ABCG2

[26]

miR-326 and SHH/GLI1 pathway

U87 and U251

↑↑ miR-326: ↑ sensitivity of cells to curcumin via inhibiting SHH/GLI1 pathway

[25]

Glioblastoma

miR-137, RTVP-1, CXCR4, Shh and Nanog

U87, HF2354, HF2355 and HF2414

↑↑ miR-137: ↓ stemness of GSCs via targeting RTVP-1

[34]

Glioma

miR-338-5p

U87 and HS683 glioma cells

Chidamide: ↓ glioma cells via increasing oxidative stress by the miR-338-5p regulation of Hedgehog signaling

[27]

Hepatocellular carcinoma

TUG1/ miR-132/shh axis

LM3, HepG2, Hep3B, Huh7, SMMC7721 and MHC97H, and LO2

↑↑ miR-132: ↓ proliferation but ↑ apoptosis via targeting shh

∆ TUG1: ↓ proliferation via targeting miR-132 and increasing Shh protein expression

[35]

Inflammatory bowel disease

NOD2, miR-146a, and NUMB

macrophages

NOD2-induced miR-146a activates SHH signaling via targeting NUMB

NOD2-iNOS/NO-miR-146a-mediated SHH Signaling increases expression of inflammatory genes

[36]

Laryngeal cancer

LINC‐PINT/ miR‐425‐5p/PTCH1 axis

HEp‐2

↑↑ LINC‐PINT: ↓ cisplatin resistance and stemness via targeting miR‐425‐5p and upregulating PTCH1 (a protein of the Hedgehog pathway)

[37]

Liver fibrosis

miR-200a/Gli2 axis

HSCs from male Sprague–Dawley rats

↑↑ miR-200a: ↓ proliferation and ↓ EMT via targeting Gli2

[38]

Lung cancer

miR-506/SHH axis

HCC4006

↑↑ miR-506-3p: ↑ sensitivity EGFR-TKI-resistant cells to Erlotinib-induced cell death, ↑ E-cadherin expression, bur ↓ SHH signaling, ↓ vimentin, thus ↓ the EMT-mediated chemoresistance

[39]

BLACAT1

A549 and PC9 cells

↑↑ BLACAT1: ↑ proliferation, migration and invasion via activating shh signaling pathway, by inducing shh, Gli-1 and Smo expression

[40]

LINC01426, USP22

HBE, H1299, A549, PC-9, Calu3

∆ LINC01426: ↓ proliferation, migration, EMT, and stemness

↑↑ LINC01426: ↑ LUAD progression via recruiting USP22 to stabilize SHH protein

[41]

Lung fibrosis

miR-193a, PI3K/Akt/mTOR and hedgehog signaling

A549 cells

↑↑ miR-193a: ↑ p-Akt, Beclin1 and LC3-II levels, thus ↑ autophagy

[42]

M. bovis BCG infection of DCs

COX-2, PD-L1, miR-324-5p and miR-338-5p

Dendritic cells

SHH signaling is required for Treg expansion in DCs via increasing COX-2 and PD-L1 and inhibiting miR-324-5p and miR-338-5p

PD-L1 was a direct target of miR-324-5p and miR-338-5p

[43]

Medulloblastoma

Arrb1, miR-326, Hh/Gli pathway

CSCs

↑↑ miR-326: ↓ proliferation and self-renewal by decreasing Smo and Gli2

[44]

Shh/Gli2/Nkx2-2as axis

Daoy and D341 Med, and HEK293T

Shh/Gli2 reduces Nkx2-2as levels by transcriptionally activating FoxD1

↑↑ Nkx2-2as1: ↓ tumorigenesis

[45]

Myocardial ischemic/reperfusion (I/R) injury

SNHG6/miR-135a-5p/HIF1AN axis and Shh/Gli1 signaling

H/R-induced cardiomyocytes

↑↑ SNHG6: ↑ H/R-induced apoptosis in cardiomyocytes via regulating miR-135a-5p/HIF1AN axis and inactivating Shh/Gli1 signaling

[46]

Neuroblastoma

miR181-a and –b, CDON

MYCN, SH-SY-5Y, SK-N-AS, IGR-N-91, NiH-3T3

↑↑ CDON: ↑ apoptosis

CDON (a receptor for SHH) is regulated by miR181-a and –b

[47]

Osteoarthritis

miR-602, miR-608

Chondrocytes and HEK 293 cells

↑↑ miR-602 and miR-608: ↓ activity of pMIR-REPORT-Luc-SHH reporter vector and ↓ IL-1β-induced endogenous SHH mRNA and protein expression in OA chondrocytes

[48]

Osteogenesis

miR-342-3p/Sufu axis, TGF-β signaling pathway

HUCMSCs

↑↑ miRNA-342-3p: ↑ expression of osteogenic genes, ↑ osteogenic differentiation of hUCMSCs and ↑ TGF-β signaling pathway via targeting Sufu

[49]

Osteogenic differentiation

miR-342-3p/Sufu axis

UCMSCs

↑↑ miR-342-3p: ↑ osteogenic differentiation via targeting Sufu and activating Shh signaling pathway

[50]

Osteonecrosis of the femoral head

miR-378-ASCs-Exos, Sufu

BMSCs and HUVECs

↑↑ miR-378-ASCs-Exos: ↑ osteogenesis and angiogenesis via targeting Sufu to increase the Shh signaling pathway, thus reducing GC-induced ONFH development

[51]

Pancreatic cancer

miR-132

MiaPaCe-2a

↑↑ miR-132: ↑ proliferation and apoptosis via targeting Shh

[24]

Retina injury

Shh Signaling/lin28a/let-7 axis

BrdU + and BrdU − and HEK293T

Downregulation of let-7 by lin28a is necessary for the regulation of Shh signaling as a part of positive feedback loop induced via the Ascl1a-lin28a axis, in turn is essential for retina regeneration

[52]

Retinoblastoma

miR-361-3p/ GLI1/3 (shh signaling) axis

Y79 and Weri-Rb-1

↑↑ miR-361-3p: ↓ proliferation and stemness via targeting GLI1 and GLI3

[53]

Skin wound healing

VEGF, miR-200 family, E-cadherin

mouse ESCs

↑↑ shh: ↑ migration and skin wound healing via increasing VEGF and negatively regulating the transcription of the miR-200 family, thus downregulating E-cadherin

[54]

Stroke

miR17-92 cluster

SVZ neural progenitor cells from adult mice

↑↑ miR17-92 Cluster: ↑ proliferation and survival of SVZ neural progenitor cells

miR17-92 cluster expression is mediated by Shh signaling

[55]

Thyroid cancer

miR-141-3p, BRD4, and PI3K/AKT pathways

Nthy-ori 3–1 and TPC-1

Propofol treatment: ↓ proliferation, migration, and invasion via ↑ miR-141-3p, and in turn ↓ BRD4, thus inhibiting the activity of SHH and PI3K/AKT pathways

[56]