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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