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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

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-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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Related in: MedlinePlus

GAPLINC regulated tumor-related proteins under hypoxia and their levels were increased in solid tumors under simulated hypoxic conditions. (A) GAPLINC ablation upregulated Bcl-2, CD44, and TGFBR2 and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (*P < 0.05 vs. the respective control group). (B) Nude mice were treated with the anti-angiogenesis agent bevacizumab or vehicle only. HIF-1α was induced in tumor xenografts treated with bevacizumab. (C) GAPLINC expression was upregulated in the bevacizumab group compared with the PBS groups (*P < 0.05, **P < 0.05).
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Figure 7: GAPLINC regulated tumor-related proteins under hypoxia and their levels were increased in solid tumors under simulated hypoxic conditions. (A) GAPLINC ablation upregulated Bcl-2, CD44, and TGFBR2 and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (*P < 0.05 vs. the respective control group). (B) Nude mice were treated with the anti-angiogenesis agent bevacizumab or vehicle only. HIF-1α was induced in tumor xenografts treated with bevacizumab. (C) GAPLINC expression was upregulated in the bevacizumab group compared with the PBS groups (*P < 0.05, **P < 0.05).

Mentions: Despite reports that GAPLINC increases GC invasiveness by rescuing CD44 from miR-211, we next examined functional proteins related to tumor growth and invasiveness. Since GAPLINC can absorb miR-211, which increases Bcl-2, and Bcl-2 abrogation upregulates the apoptotic protein Bax, Bcl-2, and Bax expressions were detected. As shown in Figure 7A, GAPLINC ablation upregulated Bcl-2, increased the CD44 content, and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (P < 0.05). This could partly account for the phenomenon that GAPLINC rescues cell viability and invasiveness under poor oxygen conditions.


Hypoxia Promotes Gastric Cancer Malignancy Partly through the HIF-1 α Dependent Transcriptional Activation of the Long Non-coding RNA GAPLINC
GAPLINC regulated tumor-related proteins under hypoxia and their levels were increased in solid tumors under simulated hypoxic conditions. (A) GAPLINC ablation upregulated Bcl-2, CD44, and TGFBR2 and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (*P < 0.05 vs. the respective control group). (B) Nude mice were treated with the anti-angiogenesis agent bevacizumab or vehicle only. HIF-1α was induced in tumor xenografts treated with bevacizumab. (C) GAPLINC expression was upregulated in the bevacizumab group compared with the PBS groups (*P < 0.05, **P < 0.05).
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Related In: Results  -  Collection

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Figure 7: GAPLINC regulated tumor-related proteins under hypoxia and their levels were increased in solid tumors under simulated hypoxic conditions. (A) GAPLINC ablation upregulated Bcl-2, CD44, and TGFBR2 and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (*P < 0.05 vs. the respective control group). (B) Nude mice were treated with the anti-angiogenesis agent bevacizumab or vehicle only. HIF-1α was induced in tumor xenografts treated with bevacizumab. (C) GAPLINC expression was upregulated in the bevacizumab group compared with the PBS groups (*P < 0.05, **P < 0.05).
Mentions: Despite reports that GAPLINC increases GC invasiveness by rescuing CD44 from miR-211, we next examined functional proteins related to tumor growth and invasiveness. Since GAPLINC can absorb miR-211, which increases Bcl-2, and Bcl-2 abrogation upregulates the apoptotic protein Bax, Bcl-2, and Bax expressions were detected. As shown in Figure 7A, GAPLINC ablation upregulated Bcl-2, increased the CD44 content, and downregulated Bax in MKN45 and SGC7901 cells under hypoxia (P < 0.05). This could partly account for the phenomenon that GAPLINC rescues cell viability and invasiveness under poor oxygen conditions.

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