Oncotarget

Research Papers: Pathology:

Characterization of cytoplasmic cyclin D1 as a marker of invasiveness in cancer

Noel P. Fusté, Esmeralda Castelblanco, Isidre Felip, Maria Santacana, Rita Fernández-Hernández, Sònia Gatius, Neus Pedraza, Judit Pallarés, Tània Cemeli, Joan Valls, Marc Tarres, Francisco Ferrezuelo, Xavier Dolcet, Xavier Matias-Guiu and Eloi Garí _

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Oncotarget. 2016; 7:26979-26991. https://doi.org/10.18632/oncotarget.8876

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Abstract

Noel P. Fusté1,4,*, Esmeralda Castelblanco2,5,*, Isidre Felip2,4,*, Maria Santacana2,5, Rita Fernández-Hernández1,4, Sònia Gatius2,5, Neus Pedraza1,4, Judit Pallarés2,5, Tània Cemeli1,4, Joan Valls3, Marc Tarres1,4, Francisco Ferrezuelo1,4, Xavier Dolcet2,4, Xavier Matias-Guiu2,4,5 and Eloi Garí1,4

1 Department of Cell Cycle, Lleida, Catalonia, Spain

2 Department of Oncological Pathology, Lleida, Catalonia, Spain

3 Department of Biostatistics and Epidemiology Unit of the Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Lleida, Catalonia, Spain

4 Department of Basic Medical Sciences at University of Lleida, Lleida, Catalonia, Spain

5 Department of Pathology and Molecular Genetics at Hospital Universitari Arnau de Vilanova, Lleida, Catalonia, Spain

* These authors have contributed equally to this work

Correspondence to:

Eloi Garí, email:

Xavier Matias-Guiu, email:

Xavier Dolcet, email:

Keywords: cyclin D1, tissue array, cell invasion, metastasis, Pathology Section

Received: December 22, 2015 Accepted: April 07, 2016 Published: April 20, 2016

Abstract

Cyclin D1 (Ccnd1) is a proto-oncogen amplified in many different cancers and nuclear accumulation of Ccnd1 is a characteristic of tumor cells. Ccnd1 activates the transcription of a large set of genes involved in cell cycle progress and proliferation. However, Ccnd1 also targets cytoplasmic proteins involved in the regulation of cell migration and invasion. In this work, we have analyzed by immunohistochemistry the localization of Ccnd1 in endometrial, breast, prostate and colon carcinomas with different types of invasion. The number of cells displaying membranous or cytoplasmic Ccnd1 was significantly higher in peripheral cells than in inner cells in both collective and pushing invasion patterns of endometrial carcinoma, and in collective invasion pattern of colon carcinoma. Also, the cytoplasmic localization of Ccnd1 was higher when tumors infiltrated as single cells, budding or small clusters of cells. To evaluate cytoplasmic function of cyclin D1, we have built a variant (Ccnd1-CAAX) that remains attached to the cell membrane therefore sequestering this cyclin in the cytoplasm. Tumor cells harboring Ccnd1-CAAX showed high levels of invasiveness and metastatic potential compared to those containing the wild type allele of Ccnd1. However, Ccnd1-CAAX expression did not alter proliferative rates of tumor cells. We hypothesize that the role of Ccnd1 in the cytoplasm is mainly associated with the invasive capability of tumor cells. Moreover, we propose that subcellular localization of Ccnd1 is an interesting guideline to measure cancer outcome.


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