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) | |
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) | |
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) | |
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) | |
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) | |
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) | |
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) | |
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) | |
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) | |
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 | |
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] |