Oncotarget

Research Papers: Pathology:

β-catenin interaction with NHERF1 and RASSF1A methylation in metastatic colorectal cancer patients

Laura Schirosi, Annalisa Mazzotta, Giuseppina Opinto, Rosamaria Pinto, Giusi Graziano, Stefania Tommasi, Livia Fucci, Giovanni Simone, Anita Mangia _

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Oncotarget. 2016; 7:67841-67850. https://doi.org/10.18632/oncotarget.12280

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Abstract

Laura Schirosi1, Annalisa Mazzotta1, Giuseppina Opinto1, Rosamaria Pinto2, Giusi Graziano3, Stefania Tommasi2, Livia Fucci4, Giovanni Simone4 and Anita Mangia1

1 Functional Biomorphology Laboratory, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

2 Molecular Genetics Laboratory, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

3 Scientific Direction, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

4 Pathology Department, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy

Correspondence to:

Anita Mangia, email:

Keywords: β-catenin, NHERF1, RASSF1A, methylation, metastatic colorectal cancer, Pathology Section

Received: June 30, 2016 Accepted: September 21, 2016 Published: September 27, 2016

Abstract

There is an increasing need to identify new biomarkers in colorectal cancer (CRC) to further characterize this malignancy. β-catenin plays a central role in the Wnt signaling pathway. It also binds Na+/H+ exchanger regulating factor 1 (NHERF1) and interacts with the RAS-association domain family 1, isoform A (RASSF1A), but the mechanisms of this possible crosstalk are still not fully understood. In this study, we analyzed for the first time the different subcellular expression of β-catenin, NHERF1, and RASSF1A and their relationships with RASSF1A methylation in the progression of CRC. We assessed immunohistochemical expression and RASSF1A methylation in 51 patients with stage IV colorectal cancer. Biomarker expression analysis was carried out considering the tumor-adjacent normal tissue, the primary tumor, and the paired liver metastases. Regarding the tumor compartment, it was found that cytoplasmic β-catenin expression was positively correlated to membranous (r = 0.3002, p = 0.0323) and nuclear NHERF1 (r = 0.293, p = 0.0368). In the liver metastases, instead, we found a positive correlation of cytoplasmic and nuclear β-catenin expression with RASSF1A methylation (r = 0.4019, p = 0.0068 and r = 0.3194, p = 0.0345, respectively).

In conclusion, our results showed that β-catenin was the crucial protagonist in metastatic CRC through different effector proteins involved in this developing process. In tumor tissues, β-catenin was predominantly associated with NHERF1 in a dynamic context, while interestingly in liver metastases, we noted an increase of its oncogenic function through RASSF1A inactivation.


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