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Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival

Oncogene volume 34, pages 1150–1159 (2015)Cite this article

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Abstract

The myristoylated alanine-rich C-kinase substrate (MARCKS) acts as a tumor suppressor in a variety of human neoplasms. In colorectal cancers (CRCs), MARCKS has been shown to be a preferential target of mutational inactivation in tumors following the microsatellite instability (MSI-H) pathway but little is known about its impact on intestinal carcinogenesis. To investigate the relevance of MARCKS inactivation in more detail, we analyzed 926 MSI-typed CRCs for MARCKS expression by immunohistochemistry and studied the functional consequences of MARCKS depletion in colorectal cancer cell lines. We found that loss of MARCKS expression was not restricted to MSI-H cancers but also occurred in microsatellite stable (MSS) tumors, where it was associated with an adverse outcome regarding overall survival, cancer-specific and disease-free survival (P=0.002, P=0.0018, P=0.0001, respectively; univariate analysis). In MARCKS-positive MSS colon cancer cell lines (SW480 and SW707) small interfering RNA (siRNA)-mediated knockdown of MARCKS conferred resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. This was accompanied by the downregulation of the TRAIL receptors DR4 and DR5 at the cell surface and activation of AKT signaling. Inhibition of AKT signaling and transient overexpression of wild-type MARCKS, but not of MARCKS lacking the effector domain (ED), abolished the anti-apoptotic effect. In conclusion, our data show that inactivation of MARCKS is common in CRCs and is associated with adverse outcome in MSS cancers. The finding that MARCKS acts as a mediator of apoptosis in MSS CRC cells adds a novel tumor-suppressing function to the so far established roles of MARCKS in cell motility and proliferation and can explain the prognostic effect of MARCKS depletion in MSS CRC.

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Acknowledgements

We thank the study participants and the interviewers who collected the data. We also greatly appreciate the help of the hospitals, pathology departments and cooperating institutions in recruiting patients for this study and providing tumor samples. We thank Jutta Richter, Ute Handte-Daub, Bettina Walter, Barbara Schreiber and Marina Gernold for their excellent technical assistance. H Bläker has been supported by a grant from the German Research Council (Deutsche Forschungsgemeinschaft; grant number: BL554/3-2). The DACHS study was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, grant numbers BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 390 117/1-1), the German Federal Ministry of Education and Research (grant numbers 01KH0404 and 01ER0814), and the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Heidelberg, Germany.

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  1. C Toth

    Present address: 7Current address: Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany.,

  2. W Roth and H Bläker: These authors shared senior authorship.

Authors and Affiliations

  1. Division of Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    M Bickeböller, K E Tagscherer & W Roth

  2. Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    M Bickeböller, K E Tagscherer, C Toth, P Schirmacher & W Roth

  3. Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany

    M Kloor

  4. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany

    L Jansen, H Brenner & M Hoffmeister

  5. Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany

    J Chang-Claude

  6. Department of General Pathology, Institute of Pathology, University Hospital Charité, Campus Mitte, Berlin, Germany

    H Bläker

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  1. M Bickeböller
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Bickeböller, M., Tagscherer, K., Kloor, M. et al. Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival. Oncogene 34, 1150–1159 (2015). https://doi.org/10.1038/onc.2014.40

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