Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene

Akiko Horiuchi; Takuma Hayashi; Norihiko Kikuchi; Akiko Hayashi; Chiho Fuseya; Tanri Shiozawa; Ikuo Konishi

doi:10.1002/ijc.27448

Hypoxia upregulates ovarian cancer invasiveness via the binding of HIF-1α to a hypoxia-induced, methylation-free hypoxia response element of S100A4 gene

Int J Cancer. 2012 Oct 15;131(8):1755-67. doi: 10.1002/ijc.27448. Epub 2012 Mar 14.

Authors

Akiko Horiuchi¹, Takuma Hayashi, Norihiko Kikuchi, Akiko Hayashi, Chiho Fuseya, Tanri Shiozawa, Ikuo Konishi

Affiliation

¹ Department of Obstetrics and Gynecology, Shinshu University Graduate School of Medicine, Matsumoto, Japan. aki9hori@shinshu-u.ac.jp

PMID: 22287060
DOI: 10.1002/ijc.27448

Abstract

Hypoxia is known to play important roles in the development and progression of tumors. We previously demonstrated that S100A4, a critical molecule for metastasis, was upregulated in ovarian cancer cells. Therefore, we examined the mechanisms of the upregulation of S100A4 expression in ovarian carcinoma cells, with particular attention paid to the effects of hypoxia. The expression levels of S100A4 were found to be correlated with the invasiveness of ovarian carcinoma cells in vitro and in vivo, and the upregulation of S100A4 expression was associated with hypomethylation of CpG sites in the first intron of S100A4 in ovarian carcinoma cell lines and tissues. The expression of S100A4 was increased under hypoxia and was associated with elevated invasiveness, which was inhibited by S100A4 small interfering RNA (siRNA). In addition, exposure to hypoxia reduced the methylation of hypoxia-response elements (HRE) of the S100A4 gene in a time-dependent fashion, in association with the increased binding of HIF-1α to a methylation-free HRE in ovarian carcinoma cells. These results indicate that hypoxia-induced hypomethylation plays an essential role in S100A4 overexpression and the epigenetic transformation of ovarian carcinoma cells into the "metastatic phenotype."

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma, Clear Cell / genetics
Adenocarcinoma, Clear Cell / metabolism
Adenocarcinoma, Clear Cell / pathology
Adenocarcinoma, Mucinous / genetics
Adenocarcinoma, Mucinous / metabolism
Adenocarcinoma, Mucinous / pathology
Animals
Blotting, Western
Chromatin Immunoprecipitation
Cystadenocarcinoma, Serous / genetics
Cystadenocarcinoma, Serous / metabolism
Cystadenocarcinoma, Serous / pathology
DNA Methylation*
Endometrial Neoplasms / genetics
Endometrial Neoplasms / metabolism
Endometrial Neoplasms / pathology
Female
Fluorescent Antibody Technique
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Hypoxia / physiopathology*
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Immunoenzyme Techniques
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Invasiveness
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology*
Ovary / cytology
Ovary / metabolism
Prognosis
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Real-Time Polymerase Chain Reaction
Response Elements
Reverse Transcriptase Polymerase Chain Reaction
S100 Calcium-Binding Protein A4
S100 Proteins / genetics*
S100 Proteins / metabolism

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
RNA, Messenger
RNA, Small Interfering
S100 Calcium-Binding Protein A4
S100 Proteins
S100A4 protein, human