CoChat
Sign Up
Cited by 377Cancer, Hypoxia, and MetabolismCancer Cells and MetastasisOvarian cancer diagnosis and treatment

Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells

Open access
Imai, Tsutomu, Horiuchi, Akiko, Wang, Cuiju, Oka, Kenji, Ohira, Satoshi, Nikaido, Toshio, Konishi, Ikuo·2003·The American Journal of Pathology
DOI 10.1016/s0002-9440(10)63501-8PMC PMC1868286
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s0002-9440(10)63501-8

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Hypoxia and HIFs contribute to EMT by upregulating transcriptional repressors such as SNAIL, TWIST, TCF3, ZFHX1A, and ZFHX1B, whose gene products repress CDH1.

    “Hypoxia and HIFs contribute to EMT by upregulating transcriptional repressors such as SNAIL (Imai et al., 2003), TWIST (Yang et al., 2008), TCF3, ZFHX1A, and ZFHX1B (Krishnamachary et al., 2006), whose gene products in turn repress CDH1.”

    From Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer (2016) · cites this paper as Imai et al., 2003

    The Discussion reports that hypoxia increased SNAIL expression in ovarian carcinoma cells while E-cadherin expression fell, and describes SNAIL as an E-cadherin repressor involved in epithelial–mesenchymal transition. It reports an association between nuclear HIF-1α and E-cadherin loss, but does not establish that HIF-1α upregulates SNAIL. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. Murdoch WJ: Ovarian surface epithelium, ovulation and carcinogen- esis. Biol Rev Camb Philos Soc 1996, 71:529 -543
  2. Bernstein LR, Liotta LA: Molecular mediators of interactions with extracellular matrix components in metastasis and angiogenesis. Curr Opin Oncol 1994, 6:106 -113
  3. Shiozaki H, Oka H, Inoue M, Tamura S, Monden M: E-cadherin mediated adhesion system in cancer cells. Cancer 1996, 77:1605- 1613
  4. Bukholm IK, Nesland JM, Karesen R, Jacobsen U, Borresen-Dale AL: E-cadherin and ␣-, ␤-, and ␥-catenin protein expression in relation to metastasis in human breast carcinoma. J Pathol 1998, 185:262-266
  5. Van Aken E, De Wever O, Correia da Rocha AS, Mareel M: Defective E-cadherin/catenin complexes in human cancer. Virchows Arch 2001, 439:725-751
  6. Mutch DG, Williams S: Biology of epithelial ovarian cancer. Clin Obstet Gynecol 1994, 37:406 -422
  7. Ratcliffe PJ, O'Rourke JF, Maxwell PH, Pugh CW: Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J Exp Biol 1998, 201:1153-1162
  8. Horiuchi A, Imai T, Shimizu M, Oka K, Wang C, Nikaido T, Konishi I: Hypoxia-induced changes in the expression of HIF-1␣, VEGF and cell cycle-related molecules in ovarian cancer cells. Anticancer Res 2002, 22:2697-2702
  9. Chomczynski P, Sacchi N: Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Bio- chem 1987, 162:156 -159
  10. Horiuchi A, Nikaido T, Ito K, Zhai Y, Orii A, Taniguchi S, Toki T, Fujii S: Reduced expression of calponin h1 in leiomyosarcoma of the uterus. Lab Invest 1998, 78:839 -846
  11. Mialhe A, Levacher G, Champelovier P, Martel V, Serres M, Knudsen K, Seigneurin D: Expression of E-, P-, N-cadherins and catenins in human bladder carcinoma cell lines. J Urol 2000, 164:826 -835
  12. Wang GL, Jiang BH, Rue EA, Semenza GL: Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O 2 tension. Proc Natl Acad Sci USA 1995, 92:5510 -5514
  13. Cheng CW, Wu PE, Yu JC, Huang CS, Yue CT, Wu CW, Shen CY: Mechanisms of inactivation of E-cadherin in breast carcinoma: mod- ification of the two-hit hypothesis of tumor suppressor gene. Onco- gene 2001, 20:3814 -3823
  14. Albini A, Iwamoto Y, Kleinman HK, Martin GR, Aaronson SA, Kozlow- ski JM, McEwan RN: A rapid in vitro assay for quantitating the inva- sive potential of tumor cells. Cancer Res 1987, 47:3239 -3245
  15. Auersperg N, Pan J, Grove BD, Peterson T, Fisher J, Maines-Ban- diera S, Somasiri A, Roskelley CD: E-cadherin induces mesenchy- mal-to-epithelial transition in human ovarian surface epithelium. Proc Natl Acad Sci USA 1999, 96:6249 -6254
  16. Darai E, Scoazec JY, Walker-Combrouze F, Mlika-Cabanne N, Feld- mann G, Madelenat P, Potet F: Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopatho- logic study of 60 cases. Hum Pathol 1997, 28:922-928
  17. Tomlinson JS, Alpaugh ML, Barsky SH: An intact overexpressed E-cadherin/␣, ␤-catenin axis characterizes the lymphovascular em- boli of inflammatory breast carcinoma. Cancer Res 2001, 61:5231- 5241
  18. Cai J, Ikeguchi M, Tsujitani S, Maeta M, Liu J, Kaibara N: Significant correlation between micrometastasis in the lymph nodes and re- duced expression of E-cadherin in early gastric cancer. Gastric Can- cer 2001, 4:66 -74
  19. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of hypoxia-inducible factor 1␣ in common human cancers and their metastases. Cancer Res 1999, 59:5830 -5835
  20. Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev 2000, 14:1983-1991
  21. Birner P, Schindl M, Obermair A, Breitenecker G, Oberhuber G: Expression of hypoxia-inducible factor 1␣ in epithelial ovarian tumors: its impact on prognosis and on response to chemotherapy. Clin Cancer Res 2001, 7:1661-1668
  22. Nakayama K, Kanzaki A, Hata K, Katabuchi H, Okamura H, Miyazaki K, Fukumoto M, Takebayashi Y: Hypoxia-inducible factor 1␣ (HIF-1␣) gene expression in human ovarian carcinoma. Cancer Lett 2002, 176:215-223
  23. Vukovic V, Haugland HK, Nicklee T, Morrison AJ, Hedley DW: Hy- poxia-inducible factor-1␣ is an intrinsic marker for hypoxia in cervical cancer xenografts. Cancer Res 2001, 61:7394 -7398
  24. Yamamoto S, Konishi I, Mandai M, Kuroda H, Komatsu T, Nanbu K, Sakahara H, Mori T: Expression of vascular endothelial growth factor (VEGF) in epithelial ovarian neoplasms: correlation with clinicopath- ology and patient survival, and analysis of serum VEGF levels. Br J Cancer 1997, 76:1221-1227
  25. Shweiki D, Itin A, Soffer D, Keshet E: Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogen- esis. Nature 1992, 35:843-845
  26. Wong AS, Maines-Bandiera SL, Rosen B, Wheelock MJ, Johnson KR, Leung PC, Roskelley CD, Auersperg N: Constitutive and conditional cadherin expression in cultured human ovarian surface epithelium: influence of family history of ovarian cancer. Int J Cancer 1999, 81:180 -188
  27. Beavon IR: Regulation of E-cadherin: does hypoxia initiate the meta- static cascade? Mol Pathol 1999, 52:179 -188
  28. Rashid MG, Sanda MG, Vallorosi CJ, Rios-Doria J, Rubin MA, Day ML: Posttranslational truncation and inactivation of human E-cadherin distinguishes prostate cancer from matched normal prostate. Cancer Res 2001, 61:489 -492
  29. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000, 2:84 -89
  30. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expres- sion. Nat Cell Biol 2000, 2:76 -83
  31. Risinger JI, Berchuck A, Kohler MF, Boyd J: Mutations of the E- cadherin gene in human gynecologic cancers. Nat Genet 1994, 7:98 -102
  32. Jiao W, Miyazaki K, Kitajima Y: Inverse correlation between E-cad- herin and Snail expression in hepatocellular carcinoma cell lines in vitro and in vivo. Br J Cancer 2002, 86:98 -101
  33. Yokoyama K, Kamata N, Hayashi E, Hoteiya T, Ueda N, Fujimoto R, Nagayama M: Reverse correlation of E-cadherin and snail expression in oral squamous cell carcinoma cells in vitro. Oral Oncol 2001, 37:65-71
  34. Poser I, Dominguez D, de Herreros AG, Varnai A, Buettner R, Bosser- hoff AK: Loss of E-cadherin expression in melanoma cells involves up-regulation of the transcriptional repressor Snail. J Biol Chem 2001, 276:24661-24666
  35. Stemmler MP, Hecht A, Kinzel B, Kemler R: Analysis of regulatory elements of E-cadherin with reporter gene constructs in transgenic mouse embryos. Dev Dyn 2003, 227:238 -245
  36. Beavon IR: The E-cadherin-catenin complex in tumour metastasis: structure, function and regulation. Eur J Cancer 2000, 36:1607-1620
  37. Sundfor K, Lyng H, Rofstad EK: Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix. Br J Cancer 1998, 78:822-827
  38. Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW: Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997, 38:285-289
  39. Brizel DM, Scully SP, Harrelson JM, Layfield LJ, Dodge RK, Charles HC, Samulski TV, Prosnitz LR, Dewhirst MW: Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarco- mas. Cancer Res 1996, 56:5347-5350
  40. Partridge EE, Phillips JL, Menck HR: The National Cancer Data Base report on ovarian cancer treatment in United States hospitals. Cancer 1996, 78:2236 -2246
  41. Ratcliffe PJ, Pugh CW, Maxwell PH: Targeting tumors through the HIF system. Nat Med 2000, 6:1315-1316

Cited by

Sorted by citations

Authors
Imai, T., Horiuchi, A., Wang, C., Oka, K., Ohira, S., Nikaido, T., & Konishi, I.
Affiliations
Shinshu University (JP)
Corresponding author
Horiuchi, Akiko
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2003-10
Volume
163
Issue
4
Pages
1437-1447
ISSN
0002-9440 (ISSN-L)
DOI
10.1016/s0002-9440(10)63501-8
PMC
PMC1868286
OpenAlex
W2023338540
Cited by
377
References
2
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 24 · 2021: 17 · 2020: 23 · 2019: 10 · 2018: 9 · 2017: 21 · 2016: 24 · 2015: 13 · 2014: 38 · 2013: 22 · 2012: 29
FWCI
3.73
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Ministry of Education, Culture, Sports, Science and Technology
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian cancer diagnosis and treatment
Keywords
hypoxia, E-cadherin, snails, ovarian carcinoma, HIF-1α, tumor invasion, epithelial-mesenchymal transition, peritoneal carcinomatosis, tumor progression, ovarian surface epithelial cells, SKOV3, OVCAR3
MeSH terms
Snail Family Transcription Factors, Hypoxia, DNA-Binding Proteins, Female, Humans, Immunohistochemistry, Neoplasm Invasiveness, Nuclear Proteins, Ovarian Neoplasms, RNA, Messenger, Staining and Labeling, Tissue Distribution, Transcription Factors, Tumor Cells, Cultured, Cadherins, Up-Regulation, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review