Furthermore, we identified that miR-203 modulated ADAM9 and HULC in a novel post-transcriptional regulatory mechanism. Over-expression of HULC partly rescued the miR-203-mediated antitumor effects. These results suggested that miR-203 played tumor suppressive roles by downregulating ADAM9 and HULC and indicated its potential application in cancer treatment.

miR-203 suppresses the proliferation and metastasis of hepatocellular carcinoma by targeting oncogene ADAM9 and oncogenic long non-coding RNA HULC

Glycolysis / Gluconeogenesis；Fatty acid degradation；Tyrosine metabolism；Retinol metabolism；Metabolism of xenobiotics by cytochrome P450；Drug metabolism - cytochrome P450；Metabolic pathways；Chemical carcinogenesis

MEG3 over-expression imposes another level of post-transcriptional regulation, whereas MEG3 overexpression increase the expression of the miR-664 target gene, ADH4, through competitive "sponging" miR-664.

Overexpression of Long Non-coding RNA MEG3 Inhibits Proliferation of Hepatocellular Carcinoma Huh7 Cells via Negative Modulation of miRNA-664

Apoptosis；MAPK signaling pathway；Acute myeloid leukemia；ErbB signaling pathway；Chemokine signaling pathway；Fc gamma R-mediated phagocytosis；Insulin signaling pathway；Pathways in cancer；Melanoma；Dopaminergic synapse；Colorectal cancer；Estrogen signaling pathway；HTLV-I infection；Toll-like receptor signaling pathway；Glioma；Adipocytokine signaling pathway；HIF-1 signaling pathway；Jak-STAT signaling pathway；Proteoglycans in cancer；Toxoplasmosis；B cell receptor signaling pathway；Small cell lung cancer；Progesterone-mediated oocyte maturation；Non-small cell lung cancer；Measles；Fc epsilon RI signaling pathway；mTOR signaling pathway；PI3K-Akt signaling pathway；Chagas disease (American trypanosomiasis)；Hepatitis C；VEGF signaling pathway；Prostate cancer；Renal cell carcinoma；Tuberculosis；Influenza A；T cell receptor signaling pathway；Osteoclast differentiation；Carbohydrate digestion and absorption； Endometrial cancer；Pancreatic cancer；Chronic myeloid leukemia；Cholinergic synapse；Hepatitis B；Focal adhesion；Epstein-Barr virus infection； Neurotrophin signaling pathway；Tight junction

Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-β-activated kinase 1 (TAK1).

The long non-coding RNA, SNHG6-003, functions as a competing endogenous RNA to promote the progression of hepatocellular carcinoma

Apoptosis；MAPK signaling pathway；Acute myeloid leukemia；ErbB signaling pathway；Chemokine signaling pathway；Fc gamma R-mediated phagocytosis；Insulin signaling pathway；Pathways in cancer；Melanoma；Dopaminergic synapse；Colorectal cancer；Estrogen signaling pathway；HTLV-I infection；Toll-like receptor signaling pathway；Glioma；Adipocytokine signaling pathway；HIF-1 signaling pathway；Jak-STAT signaling pathway；Proteoglycans in cancer；Toxoplasmosis；B cell receptor signaling pathway；Small cell lung cancer；Progesterone-mediated oocyte maturation；Non-small cell lung cancer；Measles；Fc epsilon RI signaling pathway；mTOR signaling pathway；PI3K-Akt signaling pathway；Chagas disease (American trypanosomiasis)；Hepatitis C；VEGF signaling pathway；Prostate cancer；Renal cell carcinoma；Tuberculosis；Influenza A；T cell receptor signaling pathway；Osteoclast differentiation；Carbohydrate digestion and absorption； Endometrial cancer；Pancreatic cancer；Chronic myeloid leukemia；Cholinergic synapse；Hepatitis B；Focal adhesion；Epstein-Barr virus infection； Neurotrophin signaling pathway；Tight junction

Moreover, SNHG6-003 functioned as a competitive endogenous RNA (ceRNA), effectively becoming sponge for miR-26a/b and thereby modulating the expression of transforming growth factor-β-activated kinase 1 (TAK1).

The long non-coding RNA, SNHG6-003, functions as a competing endogenous RNA to promote the progression of hepatocellular carcinoma

Regulation of autophagy；RIG-I-like receptor signaling pathway；Shigellosis

Further experiments identified: HNF1A-AS1-miR-30b axis significantly promoted autophagy under starvation and ATG5 was first proved to be a target of miR-30b.

Long non-coding RNA HNF1A-AS1 functioned as an oncogene and autophagy promoter in hepatocellular carcinoma through sponging hsa-miR-30b-5p

Bacterial invasion of epithelial cells；Wnt signaling pathway；Hippo signaling pathway；Arrhythmogenic right ventricular cardiomyopathy (ARVC)；Focal adhesion；Colorectal cancer；Adherens junction；Tight junction；Leukocyte transendothelial migration；Melanogenesis；Prostate cancer；Basal cell carcinoma；Pathogenic Escherichia coli infection；HTLV-I infection；Endometrial cancer；Proteoglycans in cancer；Pathways in cancer；Thyroid cancer

Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1.

Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB2

Bacterial invasion of epithelial cells；Wnt signaling pathway；Hippo signaling pathway；Arrhythmogenic right ventricular cardiomyopathy (ARVC)；Focal adhesion；Colorectal cancer；Adherens junction；Tight junction；Leukocyte transendothelial migration；Melanogenesis；Prostate cancer；Basal cell carcinoma；Pathogenic Escherichia coli infection；HTLV-I infection；Endometrial cancer；Proteoglycans in cancer；Pathways in cancer；Thyroid cancer

Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1.

Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1

Bacterial invasion of epithelial cells；Wnt signaling pathway；Hippo signaling pathway；Arrhythmogenic right ventricular cardiomyopathy (ARVC)；Focal adhesion；Colorectal cancer；Adherens junction；Tight junction；Leukocyte transendothelial migration；Melanogenesis；Prostate cancer；Basal cell carcinoma；Pathogenic Escherichia coli infection；HTLV-I infection；Endometrial cancer；Proteoglycans in cancer；Pathways in cancer；Thyroid cancer

Association of DANCR with CTNNB1 blocked the repressing effect of microRNA (miR)-214, miR-320a, and miR-199a on CTNNB1.

Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB3

Moreover, TUSC7 inhibited cell metastasis, invasion, and epithelial-to-mesenchymal transformation (EMT) through competitively binding miR-10a. Furthermore, we found that TUSC7 could decrease the expression of Eph tyrosine kinase receptor A4 (EphA4), a downstream target of miR-10a as well as an EMT suppressor, through TUSC7-miR-10a-EphA4 axis.

Long non-coding RNA TUSC7 acts a molecular sponge for miR-10a and suppresses EMT in hepatocellular carcinoma

MAPK signaling pathway；PI3K-Akt signaling pathway；Adherens junction；Regulation of actin cytoskeleton；Pathways in cancer；Proteoglycans in cancer；Prostate cancer；Melanoma

In addition, UCA1 could reverse the inhibitory effect of miR-216b on the growth and metastasis of HCC cells, which might be involved in the derepression of fibroblast growth factor receptor 1 (FGFR1) expression, a target gene of miR-216b, and the activation of ERK signaling pathway.

Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway

Taken together, these results suggest that HOTAIR is a FOXC1-activated driver of malignancy, which acts in part through the repression of miR-1.

HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma

Pathways in cancer；Renal cell carcinoma

It was HIF-2α, but not HIF-1α induced MALAT1 upregulation in HCC cells. Dual luciferase assay demonstrated that there were at least two binding sites of miR-26b in MALAT1.

The HIF-2α-MALAT1-miR-216b axis regulates multi-drug resistance of hepatocellular carcinoma cells via modulating autophagy

Base excision repair

By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3'UTR of HMGB1； TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1.

The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation

MAPK signaling pathway

SNHG12 functioned as an endogenous sponge for miR-199a/b-5p to regulate the expression of MLK3 and affect the NF-κB pathway.

Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma

MAPK signaling pathway

SNHG12 functioned as an endogenous sponge for miR-199a/b-5p to regulate the expression of MLK3 and affect the NF-κB pathway.

Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma

GnRH signaling pathway

ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16.

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16.

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

Proteoglycans in cancer

Moreover, GAS5 that upregulated or downregulated the expression of PDCD4 and PTEN was reversed by inhibiting or overexpressing miR-21 level in Bel-7402 and HCCLM3 cells.

Long noncoding RNA GAS5 suppresses the migration and invasion of hepatocellular carcinoma cells via miR-21

HIF-1 signaling pathway；T cell receptor signaling pathway；Fc epsilon RI signaling pathway；Neurotrophin signaling pathway；Toxoplasmosis；Hepatitis C；Proteoglycans in cancer

In addition, we revealed that there was reciprocal repression between XIST and miR-139-5p. PDK1 was identified as a direct target of miR-139-5p.

Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma

p53 signaling pathway；Inositol phosphate metabolism；Prostate cancer；Phosphatidylinositol signaling system；mTOR signaling pathway；PI3K-Akt signaling pathway；Focal adhesion；Tight junction；Hepatitis B；Pathways in cancer；Melanoma；Endometrial cancer；Glioma；Small cell lung cancer

MiR-181a was up-regulated in HCC tissues and its expression level in metastatic HCC tissues was much higher than in non-metastasis samples. PTEN was found to be a target gene of miR-181a. MiR-181a had multiple binding sites with the long non-coding RNA (lncRNA) XIST.

Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression

p53 signaling pathway；Inositol phosphate metabolism；Prostate cancer；Phosphatidylinositol signaling system；mTOR signaling pathway；PI3K-Akt signaling pathway；Focal adhesion；Tight junction；Hepatitis B；Pathways in cancer；Melanoma；Endometrial cancer；Glioma；Small cell lung cancer

Moreover, GAS5 that upregulated or downregulated the expression of PDCD4 and PTEN was reversed by inhibiting or overexpressing miR-21 level in Bel-7402 and HCCLM3 cells.

Long noncoding RNA GAS5 suppresses the migration and invasion of hepatocellular carcinoma cells via miR-21

By using luciferase assays, we confirmed that miR-200a could directly bind to TP73-AS1 and the 3'UTR of HMGB1； TP73-AS1 competed with HMGB1 for miR-200a binding. MiR-200a inhibition could up-regulate HMGB1, RAGE, NF-κB expression as well as NF-κB regulated cytokines levels, which could be partially restored by si-TP73-AS1.

The long non-coding RNA TP73-AS1 modulates HCC cell proliferation through miR-200a-dependent HMGB1/RAGE regulation

NF-kappa B signaling pathway；RIG-I-like receptor signaling pathway；Cytosolic DNA-sensing pathway；Hepatitis C；Hepatitis B；Measles；Influenza A；Herpes simplex infection；Epstein-Barr virus infection

LncRNA Ftx/miR-545-mediated downregulation of RIG-I led to increased Akt phosphorylation in vitro and in vivo.

Ftx non coding RNA-derived miR-545 promotes cell proliferation by targeting RIG-I in hepatocellular carcinoma

Hippo signaling pathway；Adherens junction

Mechanistically, Unigene56159 could directly bind to miR-140-5p and effectively act as a competing endogenous RNA (ceRNA) for miR-140-5p to de-repress the expression of the target gene Slug.

Long non-coding RNA Unigene56159 promotes epithelial-mesenchymal transition by acting as a ceRNA of miR-140-5p in hepatocellular carcinoma cells

Endocytosis；TGF-beta signaling pathway；Hippo signaling pathway

Functionally, miR-92b could promote cell proliferation and metastasis of HCC in vitro and in vivo. Mechanistic investigations suggested that Smad7, which exhibited an inverse relationship with miR-92b expression in HCC, was a direct target of miR-92b and could reverse its effects on HCC tumorigenesis. Furthermore, long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) and miR-92b could directly interact with and repress each other, and XIST could inhibit HCC cell proliferation and metastasis by targeting miR-92b.

MicroRNA-92b promotes hepatocellular carcinoma progression by targeting Smad7 and is mediated by long non-coding RNA XIST

Hippo signaling pathway；Adherens junction

Our results identified that UCA1/miR-203/Snail2 pathway might involve in HCC progression. Inhibition of UCA1 acted as a promising therapeutic target for HCC patients.

Long non-coding RNA UCA1 regulates the expression of Snail2 by miR-203 to promote hepatocellular carcinoma progression

NF-kappa B signaling pathway；MAPK signaling pathway；Ubiquitin mediated proteolysis；Endocytosis；Chagas disease (American trypanosomiasis)；Osteoclast differentiation；Toll-like receptor signaling pathway；Herpes simplex infection；NOD-like receptor signaling pathway；Hepatitis C；RIG-I-like receptor signaling pathway；Neurotrophin signaling pathway； Toxoplasmosis；Measles；Pertussis；Leishmaniasis；Tuberculosis；Small cell lung cancer；Epstein-Barr virus infection；Pathways in cancer

Remarkably, TNF receptor associated factor 6 (TRAF6) was confirmed as a direct target of miR-146b-5p in HCC and miR-146b-5p exerted the tumor suppression roles through inhibiting the phosphorylation of Akt mediated by TRAF6. Furthermore, we identified long non-coding RNA MALAT1 as a molecular sponge of miR-146b-5p to down-regulate its expression in HCC.

Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis

Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22.

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22.

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3'-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22.

LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells

Transcriptional misregulation in cancer

ZFAS1 functions as an oncogene in HCC progression by binding miR-150 and abrogating its tumor-suppressive function in this setting. miR-150 repressed HCC cell invasion by inhibiting ZEB1 and the matrix metalloproteinases MMP14 and MMP16.

Amplification of Long Noncoding RNA ZFAS1 Promotes Metastasis in Hepatocellular Carcinoma

Transcriptional misregulation in cancer

We conclude that the HULC functioned as a competing endogenous RNA (ceRNA) to mediate EMT via up-regulating ZEB1. In this way, it sequesters the miR-200a-3p signaling pathway to facilitate HCC metastasis.

LncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway