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Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis

Oncogene volume 36, pages 3104–3118 (2017)Cite this article

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Abstract

Survival signaling is critical for the metastatic program of cancer cells. The current study investigated the role of Akt survival proteins in colorectal cancer (CRC) metastasis and explored potential mechanisms of Akt-mediated metastasis regulation. Using an orthotopic implantation model in mice, which uniquely recapitulates the entire multistep process of CRC metastasis, combined with an inducible system of short hairpin RNA-mediated Akt isoform knockdown in human CRC cells, our studies confirm a role of Akt2 in CRC cell dissemination to distant organs in vivo. Akt2 deficiency profoundly inhibited the development of liver lesions in mice, whereas Akt1 had no effect under the experimental conditions used in the study. Array analysis of human metastatic genes identified the scaffolding protein metastasis suppressor 1 (MTSS1) as a novel Akt2-regulated gene. Inducible loss of Akt2 in CRC cells robustly upregulated MTSS1 at the messenger RNA and protein level, and the accumulated protein was functionally active as shown by its ability to engage an MTSS1-Src-cortactin inhibitory axis. MTSS1 expression led to a marked reduction in levels of functional cortacin (pcortactin Y421), an actin nucleation-promoting factor that has a crucial role in cancer cell invasion and metastasis. MTSS1 was also shown to mediate suppressive effects of Akt2 deficiency on CRC cell viability, survival, migration and actin polymerization in vitro. The relevance of these findings to human CRC is supported by analysis of The Cancer Genome Atlas (TCGA) and NCBI GEO data sets, which demonstrated inverse changes in expression of Akt2 and MTSS1 during CRC progression. Taken together, the data identify MTSS1 as a new Akt2-regulated gene, and point to suppression of MTSS1 as a key step in the metastasis-promoting effects of Akt2 in CRC cells.

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Acknowledgements

This work was supported by NIH R01 grants CA038173 and CA054807 to MGB, by DK60632 to JDB and by UNMC Cancer Center Support Grant CA036727. We thank Katie Bailey for assistance with animal surgeries; Dr Adrian Black for critical reading of the manuscript and many helpful discussions, as well as analysis of Oncomine data; Drs Babu Guda and Xiao Peng (Bioinformatics and Systems Biology Core, UNMC) for help with The Cancer Genome Atlas database, and the Confocal Imaging and Histology Cores at UNMC for assistance with tissue processing and microscopy.

Author contributions

Conception and design: Agarwal E, Chowdhury S and Brattain MG; development of methodology: Agarwal E; analysis and interpretation of data: Agarwal E, Chowdhury S, Brattain MG, Wang JJ and Black JD; statistical analysis of TCGA data sets: Smith LM; writing, review and/or revision of the manuscript: Agarwal E, Chowdhury S, Brattain MG, Wang JJ and Black JD; animal surgeries and dissection of animals: Agarwal E and Robb C.

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  1. M G Brattain: Deceased.

Authors and Affiliations

  1. Eppley Institute for Research in Cancer, University of Nebraska Medical Center, Omaha, Nebraska, USA

    E Agarwal, C M Robb, M G Brattain, J Wang & J D Black

  2. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    E Agarwal & M G Brattain

  3. Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA

    L M Smith

  4. Department of Medicine, Section of Gastroenterology, Boston University Medical Center, Boston, MA, USA

    S Chowdhury

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Agarwal, E., Robb, C., Smith, L. et al. Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis. Oncogene 36, 3104–3118 (2017). https://doi.org/10.1038/onc.2016.460

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