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Table 2 Hypoxia-associated lncRNA-mediated HIF signaling control and cancer progression

From: Long non-coding RNA and tumor hypoxia: new players ushered toward an old arena

lncRNA Cancer Types Clinical association Regulatory effect Mechanism Refs
LncRNAs modulating HIF pathway
ENST00000480739 Pancreatic ductal adenocarcinoma • Downregulation in PDAC
• Expression negatively associated with tumor node metastasis (TNM) stage and lymph node metastasis
• Independent risk factor for PDAC survival following surgery.
↓ Invasion
OS-9 mRNA & protein
Transcriptional regulation
(ENST00000480739 induces OS-9 expression at the transcriptional level)
[69, 77]
RERT-lncRNA Hepatocellular
carcinoma
The expression levels of RERT-lncRNA and EGLN2 were significantly correlated in HCC ↑ EGLN2 expression Transcriptional regulation
(RERT-lncRNA induces EGLN2/PHD1 expression at the transcriptional level)
[78]
HIF2PUT Osteosarcoma Expression of HIF2PUT is correlated with HIF2A mRNA ↓ Cell proliferation and migration
↓ Expression of CSC marker CD133
↓ Sphere-forming ability
Transcriptional regulation
(HIF2A mRNA expression was co-regulated with HIF2PUT expression)
[79]
LncHIFCAR Oral cancer • Upregulation in oral cancer
• High levels of LncHIFCAR predicted worse overall survival and recurrence-free survival
↑ Hypoxic glycolysis
↑ Tumor growth
Transcriptional regulation
(LncHIFCAR acts as HIF-1α coactivator)
[64]
lncRNA-LET Lung squamous-cell cancer, hepatocellular
Carcinoma and colorectal cancer
Downregulation in LSCC, HCC and CRC ↓ Metastasis
↓ Invasion
mRNA stability control
(The association between lncRNA-LET and NF90 protein enhanced the degradation of NF90, thereby decreasing HIF1A mRNA)
[68, 80]
HIF1A-AS2 Renal cell carcinoma, Glioblastoma Upregulation in non- papillary clear-cell renal carcinoma and glioblastoma ↑ Growth of M-GSCs
↑ Neurosphere-forming capacity of M-GSCs
↑ Glioblastoma tumor growth
mRNA stability control
(Binding of HIF1A-AS2 to the HIF1A mRNA 3′-UTR could expose AU-rich elements and thus increase the degradation of HIF1A mRNA)
[62, 73, 82, 85]
Scaffold of RNP complex
(The direct interaction among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 is needed for maintenance of expression of their target gene, HMGA1)
linc-ROR Hepatocellular cancer N.D. ↑ Cell viability during hypoxia
↑ Tumor growth
Sequestration of miRNAs
(Downregulation of miR145-mediated repression of P70S6K1 expression)
[49]
PVT1 Gastric cancer • Upregulation in TNBC
• High expression levels of PVT1 correlated with advanced tumor stage and lymph node metastasis
↑ GC cell proliferation
↑ GC cell invasion
Sequestration of miRNAs
(Downregulation of miR-186-mediated repression of HIF-1α expression)
[89]
lincRNA-p21 Cervical, lung and breast cancer cell lines N.D. ↑ Hypoxic glycolysis
↑ Tumor growth
Protein-Protein Interaction Decoy
(Stabilization of HIF-1α by disrupting the VHL-HIF-1α Interaction)
[61]
LINK-A Triple-negative breast cancer • Upregulation in TNBC
• High levels of LINK-A correlated with unfavorable recurrence-free survival for breast cancer patients
↑ Glycolysis
↑ Tumor growth
Scaffold of RNP complex
(LINK-A facilitates the recruitment of BRK and BRK kinase activation, thereby causing HIF-1α stabilization, HIF-1α/p300 interaction, and activation of HIF-1α transcriptional programs under normoxic conditions)
[96]
LncRNAs modulating hypoxia response through a peripheral mechanism rather than directly on HIF pathway
WT1-AS Myeloid Leukemia • Upregulation in Wilms’ tumors
• Aberrant WT1-AS splicing often found in acute myeloid leukemia
N.D. Epigenetic regulation
(WT1-AS mediate hypoxia-induced WT-1 mRNA upregulation through modulating histone methylation)
[63, 125]
lncRNA-AK058003 Gastric cancer Upregulation in GC ↑ Invasion & migration
↑ Metastasis
Epigenetic regulation
(AK058003 expression is positively correlated with SNCG expression and SNCG promoter demethylation)
[50]
HINCUT-1 (uc.475) Colon and breast cancer cell lines N.D. ↑ Hypoxic cell proliferation Transcriptional regulation
(HINCUT-1 is required for the expression of OGT mRNA expression and global O-GlcNAcylation of proteins)
[58]
GAPLINC Gastric cancer • Upregulation in GC
• High expression of GAPLINC correlates with poorer survival
• GAPLINC correlates with CD44 activation in GC tissues
↑ Proliferation
↓ Apoptosis
↑ Invasion
↑ Migration
Sequestration of miRNAs
(Downregulation of miR-211–3p-mediated repression of CD44)
[60, 90]
lncRNA-EFNA3 Breast cancer A strong correlation between high EFNA3
expression and shorter metastasis-free survival in breast cancer patients
↑ Cell extravasation
↑ Metastatic dissemination
Sequestration of miRNAs
(Downregulation of miR-210-mediated repression of EFNA3)
[57]
NUTF2P3–001 Pancreatic cancer • Upregulation in pancreatic cancer
• A positive correlation between lncRNA-NUTF2P3–001 and KRAS, which is associated with advanced tumor stage and worse prognosis.
↑ Cell viability, proliferation
↑ Invasion
↑ KRAS expression
↑ Metastasis
Sequestration of miRNAs
(Downregulation of miR-3923-mediated repression of KRAS)
[56]
H19 Glioblastoma, hepatocellular
carcinoma, bladder cancer and a large group of tumors
• Increased expression of H19 RNA is shown in a large group of tumors
• Upregulation in HCC cancer
H19 overexpression confers a poor prognosis for GBM patients
↑ Hypoxia-driven invasion & migration
↑ Tumor growth
Sequestration of miRNAs
(Downregulation of miR-181d-mediated repression of β-catenin expression)
[54, 71, 72, 122]
Transcriptional regulation
(Activation of downstream target gene involved in angiogenesis, survival and tumorigenesis through unclear mechanism)
lncRNA-SARCC Renal cell carcinoma Differentially regulated by hypoxia in a von Hippel-Lindau (VHL)-dependent manner in RCC clinical specimens. ↑ Hypoxic cell cycle progression (VHL-restored RCC cells)
↓ Hypoxic cell cycle progression (VHL-mutant RCC cells)
Control of protein activity
(LncRNA-SARCC can post-transcriptionally regulate AR by physically binding and destabilizing AR protein to suppress AR/HIF-2α/C-MYC signals)
[70]
MALAT1 Breast cancer, neuroblastoma, hepatocellular carcinoma, HUVECs Associated with poor clinical outcome in multiple cancers ↑ Cell growth
↑ Glycolysis
↑ Migration & invasion
↑ Vasculature formation
↑ Metastasis
Scaffold of RNP complex
(Affects recruitment of splicing factors to the nuclear speckles and splicing patterns of alternative exons)
[51, 74, 99, 102, 103, 122, 124, 126]
Protein-Protein Interaction Decoy
(Causes disassociation of the VHL protein from HIF-1α/HIF-2α)
NEAT1 Breast cancer High expression of NEAT1 is associated with poor survival of breast cancer patients ↑ Proliferation
↓ Apoptosis
↑ Clonogenic survival
↑ Paraspeckle formation
Scaffold of RNP complex
(Induces paraspeckle formation, thereby enhancing cancer cell survival in hypoxia)
[51, 74, 104, 105]
LncRNAs modulating hypoxia response via unclear mechanisms
HOTAIR Non-small cell lung carcinoma High level of HOTAIR is associated with poor clinical outcome in multiple cancers ↑ Cell proliferation under hypoxia
↑ Invasion & migration under hypoxia
↓ Apoptosis under hypoxia
Unclear mechanism
(Possibly through epigenetic modification)
[53, 127]
ANRIL Osteosarcoma Upregulation in osteosarcoma ↑ Hypoxic viability
↑ Hypoxia-induced Invasion
↓ Hypoxia-induced apoptosis
Unclear mechanism
(Possibly through epigenetic modification)
[59]
UCA1 Bladder cancer • Upregulation in bladder cancer
UCA1 expression associated with the clinical stage and histologic grade of bladder cancer
↑ Cell proliferation under hypoxia
↑ Invasion & migration under hypoxia
↓ Apoptosis under hypoxia
Unclear mechanism [55, 123]
PVT1 Cervical Cancer • Upregulation in ICC tissue
• High expression of PVT1 correlates with poorer overall survival
↑ Cell proliferation
↑ Migration and invasion
↓ Apoptosis
↑ Cisplatin resistance
Unclear mechanism
(Possible involvement of the interaction with Nucleolin)
[67]
  1. Abbreviation: CRC colorectal cancer, CSC cancer stem cell, GC Gastric cancer, HCC hepatocellular cancer, HUVECs Human umbilical vein endothelial cells, ICC Immunocytochemistry, LC lung cancer, M-GSCs Mesenchymal glioblastoma multiforme stem-like cells, N.D. Not determined, NSCLC nonsmall cell lung carcinoma, OSCC Oral squamous cell carcinoma, PDAC pancreatic ductal adenocarcinoma, RCC Renal Cell Carcinoma, RNP ribonucleic protein, VHL von Hippel-Lindau protein