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.
Highlights
Metastasis is the main reason for many solid tumors to be life-threatening
As we have previously shown that Fra-1 is largely dispensable for human breast cancer cell growth in vitro but crucial for their ability to metastasize in vivo [7], we decided to investigate whether Fra-1 has a similar role in human colon cancer
We demonstrate that Fra-1 is a critical biological determinant of colon cancer metastasis, as judged by two main observations
Summary
The metastatic cascade involves several steps, ranging from dissemination from the primary tumor to growth at a secondary site. The acquisition of metastatic capability by tumor cells can be associated with Epithelial-Mesenchymal Transition (EMT). Upon EMT, tumor cells are able to invade through the basement membrane of the primary tissue and stroma, and to enter the blood circulation. They often become anoikis resistant, which allows them to survive in the absence of attachment. They associate with the endothelium and extravasate to a secondary tissue. It is crucial to predict metastatic potential of disease and to target metastasis
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