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Hypoxia Promotes Gastric Cancer Malignancy Partly through the HIF-1 α Dependent Transcriptional Activation of the Long Non-coding RNA GAPLINC

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ABSTRACT

Hypoxia-inducible factor (HIF) activates the transcription of genes involved in cancer progression. Recently, HIF was reported to regulate the transcription of non-coding RNAs. Here, we show that the transcription of a long non-coding RNA (lncRNA), Gastric Adenocarcinoma Associated, Positive CD44 Regulator, Long Intergenic Non-Coding RNA (GAPLINC), is directly activated by HIF-1α in gastric cancer (GC). GAPLINC was overexpressed in GC tissues and promoted tumor migration and invasive behavior. GAPLINC overexpression was associated with poor prognosis in GC patients. Luciferase reporter assays and chromatin immunoprecipitation assays confirmed that HIF-1α binds to the promoter region of GAPLINC and activates its transcription. GAPLINC knockdown inhibited hypoxia-induced tumor proliferation in vivo. Taken together, our results identified a novel role for HIF transcriptional pathways in GC tumorigenesis mediated by the regulation of the lncRNA GAPLINC, and suggest GAPLINC as a novel therapeutic target for reversing chemoradioresistance and prolonging survival.

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GAPLINC expression was induced under hypoxia mainly by HIF-1α. Data represent the mean ± SD. (A) HIF-1α and HIF-2α were upregulated in MKN45 and SGC7901 cells under hypoxic conditions. (B) GAPLINC was upregulated under hypoxia in MKN45 and SGC7901 cells. (C) qPCR analysis of the normoxic expression of GAPLINC in MKN45 and SGC7901 cells following transfection with control siRNA, HIF-1α siRNA, or HIF-2α siRNA. (D) The same experiments were performed in hypoxia, demonstrating marked dependence on HIF-1α (*P < 0.05, **P < 0.05).
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Figure 2: GAPLINC expression was induced under hypoxia mainly by HIF-1α. Data represent the mean ± SD. (A) HIF-1α and HIF-2α were upregulated in MKN45 and SGC7901 cells under hypoxic conditions. (B) GAPLINC was upregulated under hypoxia in MKN45 and SGC7901 cells. (C) qPCR analysis of the normoxic expression of GAPLINC in MKN45 and SGC7901 cells following transfection with control siRNA, HIF-1α siRNA, or HIF-2α siRNA. (D) The same experiments were performed in hypoxia, demonstrating marked dependence on HIF-1α (*P < 0.05, **P < 0.05).

Mentions: Accumulating evidence indicates that the hypoxic microenvironment provides an important niche for drug-resistant cells (Brown, 1990; Trédan et al., 2007; Lin et al., 2011). HIF, as a finely regulated transcriptional factor, could stably exist in the hypoxic environment in MKN45 and SGC7901 cells (Figure 2A). To investigate the effect of hypoxia on GAPLINC expression, GAPLINC levels were monitored under conditions of normoxia and hypoxia. GAPLINC expression was gradually upregulated in both cell lines in a hypoxic atmosphere, and after 24 h the difference became significant (Figure 2B, P < 0.01). Knockdown of the two active subunits of HIF (HIF-1α and HIF-2α) did not affect GAPLINC expression under normoxia, whereas GAPLINC was markedly downregulated under hypoxia. The reduction was more obvious in the siHIF-1α group (Figures 2C,D).


Hypoxia Promotes Gastric Cancer Malignancy Partly through the HIF-1 α Dependent Transcriptional Activation of the Long Non-coding RNA GAPLINC
GAPLINC expression was induced under hypoxia mainly by HIF-1α. Data represent the mean ± SD. (A) HIF-1α and HIF-2α were upregulated in MKN45 and SGC7901 cells under hypoxic conditions. (B) GAPLINC was upregulated under hypoxia in MKN45 and SGC7901 cells. (C) qPCR analysis of the normoxic expression of GAPLINC in MKN45 and SGC7901 cells following transfection with control siRNA, HIF-1α siRNA, or HIF-2α siRNA. (D) The same experiments were performed in hypoxia, demonstrating marked dependence on HIF-1α (*P < 0.05, **P < 0.05).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037220&req=5

Figure 2: GAPLINC expression was induced under hypoxia mainly by HIF-1α. Data represent the mean ± SD. (A) HIF-1α and HIF-2α were upregulated in MKN45 and SGC7901 cells under hypoxic conditions. (B) GAPLINC was upregulated under hypoxia in MKN45 and SGC7901 cells. (C) qPCR analysis of the normoxic expression of GAPLINC in MKN45 and SGC7901 cells following transfection with control siRNA, HIF-1α siRNA, or HIF-2α siRNA. (D) The same experiments were performed in hypoxia, demonstrating marked dependence on HIF-1α (*P < 0.05, **P < 0.05).
Mentions: Accumulating evidence indicates that the hypoxic microenvironment provides an important niche for drug-resistant cells (Brown, 1990; Trédan et al., 2007; Lin et al., 2011). HIF, as a finely regulated transcriptional factor, could stably exist in the hypoxic environment in MKN45 and SGC7901 cells (Figure 2A). To investigate the effect of hypoxia on GAPLINC expression, GAPLINC levels were monitored under conditions of normoxia and hypoxia. GAPLINC expression was gradually upregulated in both cell lines in a hypoxic atmosphere, and after 24 h the difference became significant (Figure 2B, P < 0.01). Knockdown of the two active subunits of HIF (HIF-1α and HIF-2α) did not affect GAPLINC expression under normoxia, whereas GAPLINC was markedly downregulated under hypoxia. The reduction was more obvious in the siHIF-1α group (Figures 2C,D).

View Article: PubMed Central - PubMed

ABSTRACT

Hypoxia-inducible factor (HIF) activates the transcription of genes involved in cancer progression. Recently, HIF was reported to regulate the transcription of non-coding RNAs. Here, we show that the transcription of a long non-coding RNA (lncRNA), Gastric Adenocarcinoma Associated, Positive CD44 Regulator, Long Intergenic Non-Coding RNA (GAPLINC), is directly activated by HIF-1&alpha; in gastric cancer (GC). GAPLINC was overexpressed in GC tissues and promoted tumor migration and invasive behavior. GAPLINC overexpression was associated with poor prognosis in GC patients. Luciferase reporter assays and chromatin immunoprecipitation assays confirmed that HIF-1&alpha; binds to the promoter region of GAPLINC and activates its transcription. GAPLINC knockdown inhibited hypoxia-induced tumor proliferation in vivo. Taken together, our results identified a novel role for HIF transcriptional pathways in GC tumorigenesis mediated by the regulation of the lncRNA GAPLINC, and suggest GAPLINC as a novel therapeutic target for reversing chemoradioresistance and prolonging survival.

No MeSH data available.


Related in: MedlinePlus