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

HIF-1 signaling pathway；NF-kappa B signaling pathway；Protein processing in endoplasmic reticulum；Pathways in cancer；Small cell lung cancer；Prostate cancer；PI3K-Akt signaling pathway；Apoptosis；Focal adhesion； Neurotrophin signaling pathway；Cholinergic synapse；Amyotrophic lateral sclerosis (ALS)；Colorectal cancer；Hepatitis B；Epstein-Barr virus infection； Toxoplasmosis；Tuberculosis

Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge.

Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia

Hepatitis B；MAPK signaling pathway；ErbB signaling pathway；Cell cycle；PI3K-Akt signaling pathway；Transcriptional misregulation in cancer；Bladder cancer；Wnt signaling pathway；Colorectal cancer；Endometrial cancer；Acute myeloid leukemia；TGF-beta signaling pathway；Hippo signaling pathway；Small cell lung cancer；Proteoglycans in cancer；Thyroid cancer；Jak-STAT signaling pathway；Pathways in cancer；HTLV-I infection；Chronic myeloid leukemia；Epstein-Barr virus infection

Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge.

Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia

Dopaminergic synapse；PI3K-Akt signaling pathway；HTLV-I infection；Huntington's disease；Hepatitis B；Osteoclast differentiation；Antigen processing and presentation；Circadian rhythm；Alcoholism；Circadian entrainment；Cholinergic synapse；Prostate cancer；Viral carcinogenesis；Cocaine addiction；Tuberculosis；Insulin secretion；Estrogen signaling pathway；Melanogenesis；Amphetamine addiction；Vasopressin-regulated water reabsorption

Furthermore, we demonstrated HULC may act as an endogenous 'sponge', which down-regulates a series of microRNAs (miRNAs) activities, including miR-372. Inhibition of miR-372 leads to reducing translational repression of its target gene, PRKACB, which in turn induces phosphorylation of CREB.

CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H21 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Cytokine-cytokine receptor interaction；Chemokine signaling pathway；Endocytosis；Axon guidance；Leukocyte transendothelial migration；Intestinal immune network for IgA production

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H22 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

HTLV-I infection；Cell cycle；Hepatitis B；Non-small cell lung cancer；Pathways in cancer；Pancreatic cancer；Glioma；Prostate cancer；Melanoma；Bladder cancer；Chronic myeloid leukemia；Small cell lung cancer

HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3'UTR, by complementary base pairing.

Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1)

NOD-like receptor signaling pathway；Cytokine-cytokine receptor interaction；HIF-1 signaling pathway；PI3K-Akt signaling pathway；Toll-like receptor signaling pathway；Legionellosis；Hypertrophic cardiomyopathy (HCM)；African trypanosomiasis；Cytosolic DNA-sensing pathway；Jak-STAT signaling pathway；Hematopoietic cell lineage；Intestinal immune network for IgA production；Transcriptional misregulation in cancer；Influenza A； Herpes simplex infection；Pathways in cancer；Chagas disease (American trypanosomiasis)；Graft-versus-host disease；Malaria；Prion diseases；Pertussis；Rheumatoid arthritis；Measles；Salmonella infection；Amoebiasis；Hepatitis B；HTLV-I infection；Tuberculosis

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

NOD-like receptor signaling pathway；Cytokine-cytokine receptor interaction；HIF-1 signaling pathway；PI3K-Akt signaling pathway；Toll-like receptor signaling pathway；Legionellosis；Hypertrophic cardiomyopathy (HCM)；African trypanosomiasis；Cytosolic DNA-sensing pathway；Jak-STAT signaling pathway；Hematopoietic cell lineage；Intestinal immune network for IgA production；Transcriptional misregulation in cancer；Influenza A； Herpes simplex infection；Pathways in cancer；Chagas disease (American trypanosomiasis)；Graft-versus-host disease；Malaria；Prion diseases；Pertussis；Rheumatoid arthritis；Measles；Salmonella infection；Amoebiasis；Hepatitis B；HTLV-I infection；Tuberculosis

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

NOD-like receptor signaling pathway；Cytokine-cytokine receptor interaction；HIF-1 signaling pathway；PI3K-Akt signaling pathway；Toll-like receptor signaling pathway；Legionellosis；Hypertrophic cardiomyopathy (HCM)；African trypanosomiasis；Cytosolic DNA-sensing pathway；Jak-STAT signaling pathway；Hematopoietic cell lineage；Intestinal immune network for IgA production；Transcriptional misregulation in cancer；Influenza A； Herpes simplex infection；Pathways in cancer；Chagas disease (American trypanosomiasis)；Graft-versus-host disease；Malaria；Prion diseases；Pertussis；Rheumatoid arthritis；Measles；Salmonella infection；Amoebiasis；Hepatitis B；HTLV-I infection；Tuberculosis

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

NOD-like receptor signaling pathway；Cytokine-cytokine receptor interaction；HIF-1 signaling pathway；PI3K-Akt signaling pathway；Toll-like receptor signaling pathway；Legionellosis；Hypertrophic cardiomyopathy (HCM)；African trypanosomiasis；Cytosolic DNA-sensing pathway；Jak-STAT signaling pathway；Hematopoietic cell lineage；Intestinal immune network for IgA production；Transcriptional misregulation in cancer；Influenza A； Herpes simplex infection；Pathways in cancer；Chagas disease (American trypanosomiasis)；Graft-versus-host disease；Malaria；Prion diseases；Pertussis；Rheumatoid arthritis；Measles；Salmonella infection；Amoebiasis；Hepatitis B；HTLV-I infection；Tuberculosis

H19 and HULC functioned as competing endogenous RNAs (ceRNAs) by sponging let-7a/let-7b and miR-372/miR-373, respectively, which activate pivotal inflammation cytokine IL-6 and chemokine receptor CXCR4.

LncRNAs H19 and HULC, activated by oxidative stress, promote cell migration and invasion in cholangiocarcinoma through a ceRNA manner

Sphingolipid metabolism；Metabolic pathways；Calcium signaling pathway；VEGF signaling pathway；Fc gamma R-mediated phagocytosis；Tuberculosis

Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.

Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1)

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

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