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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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Correlation between HIF-1α protein expression and GAPLINC expression. GAPLINC overexpression was associated with adverse clinical outcomes in patients with gastric cancer (GC). Data represent the mean ± SD. (A) HIF-1α was highly expressed in human gastric tissues (n = 3 each group). (B) The endogenous expression of GAPLINC was determined by qRT-PCR in control gastric tissues, highly differentiated gastric adenocarcinoma tissues, and poorly differentiated gastric adenocarcinoma tissues. (C) Spearman correlation between HIF-1α protein expression and GAPLINC expression (R = 0.6041). (D) GAPLINC was highly expressed in GCcell lines compared to normal gastric mucosa cell lines. (E) Overall survival (OS) of patients with GAPLINC-low expression (17 cases) and high expression (16 cases). GAPLINC expressions were normalized to the ratios of expressions in tissues to one specimen picked randomly in NGTs (ranged from 1.23 to 3.24, and the cut off point was 2.03). The Mantel-Cox test was used to compare OS after surgery. The GAPLINC-low expression group had longer OS (*P < 0.05, **P < 0.01).
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Figure 1: Correlation between HIF-1α protein expression and GAPLINC expression. GAPLINC overexpression was associated with adverse clinical outcomes in patients with gastric cancer (GC). Data represent the mean ± SD. (A) HIF-1α was highly expressed in human gastric tissues (n = 3 each group). (B) The endogenous expression of GAPLINC was determined by qRT-PCR in control gastric tissues, highly differentiated gastric adenocarcinoma tissues, and poorly differentiated gastric adenocarcinoma tissues. (C) Spearman correlation between HIF-1α protein expression and GAPLINC expression (R = 0.6041). (D) GAPLINC was highly expressed in GCcell lines compared to normal gastric mucosa cell lines. (E) Overall survival (OS) of patients with GAPLINC-low expression (17 cases) and high expression (16 cases). GAPLINC expressions were normalized to the ratios of expressions in tissues to one specimen picked randomly in NGTs (ranged from 1.23 to 3.24, and the cut off point was 2.03). The Mantel-Cox test was used to compare OS after surgery. The GAPLINC-low expression group had longer OS (*P < 0.05, **P < 0.01).

Mentions: A recent study reported that the lncRNA GAPLINC is upregulated in human GC (Hu et al., 2014). Assessment of HIF-1α expression showed that it was markedly upregulated under conditions of hypoxia in GC specimens (Figure 1). Immunoblot analysis showed that HIF-1α was highly expressed in gastric adenocarcinoma, especially in poorly-differentiated tumors, compared with NGT (P < 0.05, Figure 1A). qRT-PCR results showed that the pattern of expression of GAPLINC was similar to that of HIF-1α (P < 0.05, Figure 1B). Spearman correlation analysis showed a positive correlation between GAPLINC and HIF-1α expression (R = 0.6041, P < 0.05, Figure 1C). We therefore examined the association between HIF-1α and GAPLINC in further detail. GAPLINC was expressed at higher levels in the GC cell lines MKN45 and SGC7901 than in the gastric mucosa cell lines GES-1 and HFE-145 (Figure 1D). Overall survival analysis indicated that GAPLINC overexpression was associated with poor prognosis in GC patients (P < 0.05, Figure 1E).


Hypoxia Promotes Gastric Cancer Malignancy Partly through the HIF-1 α Dependent Transcriptional Activation of the Long Non-coding RNA GAPLINC
Correlation between HIF-1α protein expression and GAPLINC expression. GAPLINC overexpression was associated with adverse clinical outcomes in patients with gastric cancer (GC). Data represent the mean ± SD. (A) HIF-1α was highly expressed in human gastric tissues (n = 3 each group). (B) The endogenous expression of GAPLINC was determined by qRT-PCR in control gastric tissues, highly differentiated gastric adenocarcinoma tissues, and poorly differentiated gastric adenocarcinoma tissues. (C) Spearman correlation between HIF-1α protein expression and GAPLINC expression (R = 0.6041). (D) GAPLINC was highly expressed in GCcell lines compared to normal gastric mucosa cell lines. (E) Overall survival (OS) of patients with GAPLINC-low expression (17 cases) and high expression (16 cases). GAPLINC expressions were normalized to the ratios of expressions in tissues to one specimen picked randomly in NGTs (ranged from 1.23 to 3.24, and the cut off point was 2.03). The Mantel-Cox test was used to compare OS after surgery. The GAPLINC-low expression group had longer OS (*P < 0.05, **P < 0.01).
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Figure 1: Correlation between HIF-1α protein expression and GAPLINC expression. GAPLINC overexpression was associated with adverse clinical outcomes in patients with gastric cancer (GC). Data represent the mean ± SD. (A) HIF-1α was highly expressed in human gastric tissues (n = 3 each group). (B) The endogenous expression of GAPLINC was determined by qRT-PCR in control gastric tissues, highly differentiated gastric adenocarcinoma tissues, and poorly differentiated gastric adenocarcinoma tissues. (C) Spearman correlation between HIF-1α protein expression and GAPLINC expression (R = 0.6041). (D) GAPLINC was highly expressed in GCcell lines compared to normal gastric mucosa cell lines. (E) Overall survival (OS) of patients with GAPLINC-low expression (17 cases) and high expression (16 cases). GAPLINC expressions were normalized to the ratios of expressions in tissues to one specimen picked randomly in NGTs (ranged from 1.23 to 3.24, and the cut off point was 2.03). The Mantel-Cox test was used to compare OS after surgery. The GAPLINC-low expression group had longer OS (*P < 0.05, **P < 0.01).
Mentions: A recent study reported that the lncRNA GAPLINC is upregulated in human GC (Hu et al., 2014). Assessment of HIF-1α expression showed that it was markedly upregulated under conditions of hypoxia in GC specimens (Figure 1). Immunoblot analysis showed that HIF-1α was highly expressed in gastric adenocarcinoma, especially in poorly-differentiated tumors, compared with NGT (P < 0.05, Figure 1A). qRT-PCR results showed that the pattern of expression of GAPLINC was similar to that of HIF-1α (P < 0.05, Figure 1B). Spearman correlation analysis showed a positive correlation between GAPLINC and HIF-1α expression (R = 0.6041, P < 0.05, Figure 1C). We therefore examined the association between HIF-1α and GAPLINC in further detail. GAPLINC was expressed at higher levels in the GC cell lines MKN45 and SGC7901 than in the gastric mucosa cell lines GES-1 and HFE-145 (Figure 1D). Overall survival analysis indicated that GAPLINC overexpression was associated with poor prognosis in GC patients (P < 0.05, Figure 1E).

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