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] |