RGD Reference Report - Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells. - Rat Genome Database

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Exon 11 skipping of E-cadherin RNA downregulates its expression in head and neck cancer cells.

Authors: Sharma, S  Liao, W  Zhou, X  Wong, DT  Lichtenstein, A 
Citation: Sharma S, etal., Mol Cancer Ther. 2011 Sep;10(9):1751-9. doi: 10.1158/1535-7163.MCT-11-0248. Epub 2011 Jul 15.
RGD ID: 11039047
Pubmed: PMID:21764905   (View Abstract at PubMed)
PMCID: PMC3170438   (View Article at PubMed Central)
DOI: DOI:10.1158/1535-7163.MCT-11-0248   (Journal Full-text)

E-cadherin is an important tumor suppressor gene whose expression is lost when cells acquire a metastatic phenotype. We analyzed the role of E-cadherin missplicing as a mechanism of its downregulation by analyzing a misspliced E-cadherin transcript that lacks exon 11 of this gene. This results in a frameshift and a premature termination codon that targets this transcript for degradation. Tumor tissues, including breast (20%, n = 9), prostate (30%, n = 9) and head and neck (75%, n = 8) cancer, express the exon 11-skipped transcripts (vs. nonmalignant controls) and its levels inversely correlate with E-cadherin expression. This is a novel mechanism of E-cadherin downregulation by missplicing in tumor cells, which is observed in highly prevalent human tumors. In the head and neck cancer model, nontumorigenic keratinocytes express exon 11-skipped splice product two- to sixfold lower than the head and neck tumor cell lines. Mechanistic studies reveal that SFRS2 (SC35), a splicing factor, as one of the regulators that increases missplicing and downregulates E-cadherin expression. Furthermore, this splicing factor was found to be overexpressed in 5 of 7 head and neck cell lines and primary head and neck tumors. Also, methylation of E-cadherin gene acts as a regulator of this aberrant splicing process. In 2 head and neck cell lines, wild-type transcript expression increased 16- to 25-folds, whereas the percentage of exon 11-skipped transcripts in both the cell lines decreased five- to 30-folds when cells were treated with a hypomethylating agent, azacytidine. Our findings reveal that promoter methylation and an upregulated splicing factor (SFRS2) are involved in the E-cadherin missplicing in tumors.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Head and Neck Neoplasms  IEP 11039047mRNA:increased expression:head and neck (human)RGD 
Head and Neck Neoplasms  ISOSRSF2 (Homo sapiens)11039047; 11039047mRNA:increased expression:head and neck (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Srsf2  (serine and arginine rich splicing factor 2)

Genes (Mus musculus)
Srsf2  (serine and arginine-rich splicing factor 2)

Genes (Homo sapiens)
SRSF2  (serine and arginine rich splicing factor 2)


Additional Information