Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells - PubMed (original) (raw)
Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells
Tsutomu Imai et al. Am J Pathol. 2003 Oct.
Abstract
Since ovarian carcinoma cells detach from the primary lesion and metastasize via peritoneal dissemination, we hypothesized that these cells are exposed to hypoxia, which may affect cell attachment and invasiveness. To address this hypothesis, we first examined in vivo the immunohistochemical expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and its topological correlation with E-cadherin expression in ovarian carcinomas. We then examined in vitro the effect of hypoxia on the mRNA and protein expressions of E-cadherin using two ovarian cancer cell lines, SKOV3 and OVCAR3, and normal ovarian surface epithelial (OSE) cells. In addition, hypoxia-induced change in the expression of SNAIL, a transcriptional factor repressing E-cadherin expression, was also analyzed. Finally, we examined the facilitation of invasiveness of ovarian cancer cells under hypoxia using Matrigel invasion assay. Immunohistochemically, nuclear localization of HIF-1alpha was observed in 32 of the 76 (42%) carcinomas studied, and showed a topological correlation with loss of E-cadherin expression. Northern blotting, real-time PCR and Western blotting demonstrated that E-cadherin expression was remarkably decreased under hypoxia in both SKOV3 and OVCAR3 cells, but not in normal OSE cells. mRNA expression of SNAIL was increased under hypoxia in both ovarian cancer cell lines. Invasion assay revealed that hypoxia increases the invasiveness of ovarian cancer cells. Accordingly, the present study demonstrated that hypoxia induces down-regulation of E-cadherin in ovarian carcinoma cells, via up-regulation of the transcriptional repressor SNAIL. These findings suggest that hypoxia plays an important role in the change in intercellular attachment, which may be involved in the initiation of tumor progression of ovarian cancer cells.
Figures
Figure 1.
Immunohistochemical staining of E-cadherin in ovarian carcinomas. a: Serous carcinoma. b: Mucinous carcinoma. c: Endometrioid carcinoma. d: Clear cell carcinoma. Magnification, ×100
Figure 2.
Immunohistochemical staining of HIF-1α in ovarian carcinoma tissues. Nuclear localization of HIF-1α is sporadically observed in the tumor cells in the tip of the papillary projection (a) or in the vicinity of necrosis (b). Cytoplasmic localization of HIF-1α is more frequently observed (c and d). a: Serous carcinoma. b: Endometrioid carcinoma. c: Serous carcinoma. d: Clear cell carcinoma. Magnification, ×100
Figure 3.
Topological correlation between HIF-1α (a and c) and E-cadherin (b and d). In the serial sections for immunolocalization of HIF-1α and E-cadherin, the tumor cells with nuclear expression of HIF-1α (a and c; arrows) are associated with reduced or loss of expression of E-cadherin (b and d; arrows), compared with the surrounding tumor cells negative for HIF-1α. Magnification, ×100
Figure 4.
Northern blot analysis showing the effect of hypoxia on E-cadherin mRNA in OSE cells and in two ovarian cancer cell lines. A: The specific bands for E-cadherin mRNAs are decreased under hypoxia in SKOV3 and OVCAR3, but not in OSE. B: The density of the bands was quantitated by densitometric analysis. Data are presented after normalization with the G3PDH bands.
Figure 5.
Western blot analysis showing the effect of hypoxia on HIF-1α and E-cadherin proteins in OSE cells and in two ovarian cancer cell lines. A: Specific bands for HIF-1α and E-cadherin were detected, and the band density of HIF-1α is increased in two ovarian cancer cells, but not in OSE cells under hypoxia. E-cadherin expression is remarkably decreased in two ovarian cancer cells, but not in OSE cells under hypoxia. B: The density of the E-cadherin bands was quantified by densitometric analysis. Data are presented after normalization with the β-actin bands.
Figure 6.
RT-PCR analysis showing the effect of hypoxia on the expression of SNAIL and E-cadherin mRNA in OSE cells and in two ovarian cancer cell lines. A: A specific band for SNAIL mRNA is detected in normoxia and is increased under hypoxia in two cultured ovarian cancer cells, but not in OSE cells. Along with SNAIL up-regulation, the expression of E-cadherin mRNA is decreased in two ovarian cancer cells, but not in OSE cells. B: The density of the bands for SNAIL was quantitated by densitometric analysis. C: The density of the bands for E-cadherin was quantitated by densitometric analysis. Data are expressed after normalization with the G3PDH bands.
Figure 7.
In vitro invasion assay showing the effect of hypoxia on the invasiveness of ovarian cancer cells. a: Photographs showing the cells that have passed through the Matrigel-coated membranes; OSE, normoxia. b: OSE, hypoxia. c: SKOV3, normoxia. d: SKOV3, hypoxia. e: OVCAR3, normoxia. f: OVCAR3, hypoxia. Original magnification, ×200. The number of both SKOV3 and OVCAR3 cells invading the Matrigel is significantly increased under hypoxic condition compared with under normoxia. Hypoxic effect was not seen in OSE cells.
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