Cited by 86RNA Research and SplicingConnective Tissue Growth Factor ResearchCancer Mechanisms and Therapy

Alternative Splicing of Cyr61 Is Regulated by Hypoxia and Significantly Changed in Breast Cancer

Hirschfeld, Marc, zur Hausen, Axel, Bettendorf, Herta, Jäger, Markus, Stickeler, Elmar·2009·Cancer Research

Abstract

Hypoxia is known to induce the transcriptional activation of pathways involved in angiogenesis, growth factor signaling, and tissue invasion and is therefore a potential key regulator of tumor growth. Cyr61 (cysteine rich 61) is a secreted, matricellular protein with proangiogenic capabilities and is transcriptionally induced under hypoxic conditions. High expression levels of Cyr61 were already detected in various cancer types and linked to tumor progression and advanced stages in breast cancer. Besides hypoxia, there is some evidence that posttranscriptional pre-mRNA processing could be involved in the regulation of Cyr61 expression, but was thus far not investigated. We studied the expression pattern of Cyr61 mRNA and protein in breast cancer cell lines as well as in matched pairs of noncancerous breast tissue, preinvasive lesions, and invasive breast cancers, respectively. In addition, we analyzed the potential regulatory capability of hypoxia on Cyr61 expression by functional tissue culture experiments. Our study revealed a stage-dependent induction of Cyr61 mRNA and protein in breast cancer tumorigenesis and for the first time alternative splicing of the Cyr61 gene due to intron retention. Breast carcinogenesis was accompanied by a shift from an intron 3 retaining toward an intron 3 skipping mRNA phenotype consecutively leading to processing of the biological active Cyr61 protein. The functional analyses strongly emphasize that hypoxia serves as a specific inducer of alternative Cyr61 splicing toward the intron skipping mRNA isoform with potential biological consequences in tumor cells. [Cancer Res 2009;69(5):2082–90]

Integrity signals

Registry

Crossref · 10.1158/0008-5472.can-08-1997

Cites

51 of 51 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

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?

  • Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate CCN1 within the central hinge region; this splicing is blocked under hypoxia in breast cancer cells, leading to full-length CCN1.

    “Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate the CCN1 polypeptide within the central hinge region. However, this alternative splicing is blocked under hypoxic conditions in breast cancer cells, leading to the synthesis of full-length CCN1 [48].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [48]

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Hirschfeld, M., zur Hausen, A., Bettendorf, H., Jäger, M., & Stickeler, E.
Affiliations
  • University Medical Center Freiburg (DE)
  • 2Institute of Pathology, Freiburg University Medical Center, Freiburg, Germany
Venue
Cancer Research
Published
2009-03-01
Volume
69
Issue
5
Pages
2082-2090
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
OpenAlex
W2021418778
Cited by
86
References
50
Citations by year
2026: 4 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 10 · 2018: 4 · 2017: 7 · 2016: 2 · 2015: 6 · 2014: 5 · 2013: 9 · 2012: 8
FWCI
3.49
Type
journal article
Language
en
Open access
closed
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords
CYR61, alternative splicing, hypoxia, breast cancer, intron retention, matricellular proteins, angiogenesis, tumor progression, preinvasive breast lesions, tumor stage, post-transcriptional regulation
MeSH terms
Breast, Breast Neoplasms, Female, Humans, Immunohistochemistry, RNA, Messenger, Cell Hypoxia, Alternative Splicing, Cell Line, Tumor, Cysteine-Rich Protein 61

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