Oncotarget

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Fra-1 is a key driver of colon cancer metastasis and a Fra-1 classifier predicts disease-free survival

Sedef Iskit, Andreas Schlicker, Lodewyk Wessels and Daniel S. Peeper _

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Oncotarget. 2015; 6:43146-43161. https://doi.org/10.18632/oncotarget.6454

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Abstract

Sedef Iskit1, Andreas Schlicker2, Lodewyk Wessels2 and Daniel S. Peeper1

1 Department of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands

2 Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, The Netherlands

Correspondence to:

Daniel S. Peeper, email:

Keywords: colon cancer, metastasis, Fra-1, in vivo, Wnt

Received: June 08, 2015 Accepted: November 14, 2015 Published: December 03, 2015

Abstract

Fra-1 (Fos-related antigen-1) is a member of the AP-1 (activator protein-1) family of transcription factors. We previously showed that Fra-1 is necessary for breast cancer cells to metastasize in vivo, and that a classifier comprising genes that are expressed in a Fra-1-dependent fashion can predict breast cancer outcome. Here, we show that Fra-1 plays an important role also in colon cancer progression. Whereas Fra-1 depletion does not affect 2D proliferation of human colon cancer cells, it impairs growth in soft agar and in suspension. Consistently, subcutaneous tumors formed by Fra-1-depleted colon cancer cells are three times smaller than those produced by control cells. Most remarkably, when injected intravenously, Fra-1 depletion causes a 200-fold reduction in tumor burden. Moreover, a Fra-1 classifier generated by comparing RNA profiles of parental and Fra-1-depleted colon cancer cells can predict the prognosis of colon cancer patients. Functional pathway analysis revealed Wnt as one of the central pathways in the classifier, suggesting a possible mechanism of Fra-1 function in colon cancer metastasis. Our results demonstrate that Fra-1 is an important determinant of the metastatic potential of human colon cancer cells, and that the Fra-1 classifier can be used as a prognostic predictor in colon cancer patients.


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