Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth.

Autor:	Cook DR; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Kang M; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Martin TD; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Galanko JA; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Loeza GH; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Trembath DG; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Justilien V; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida., Pickering KA; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Vincent DF; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Jarosch A; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany., Jurmeister P; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany., Waters AM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Hibshman PS; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Campbell AD; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Ford CA; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Keku TO; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Yeh JJ; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Lee MS; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Cox AD; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Fields AP; Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida., Sandler RS; Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Sers C; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany.; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Schaefer A; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. cjder@med.unc.edu antje_schaefer@med.unc.edu.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Der CJ; Division of Chemical Biology and Medicinal Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. cjder@med.unc.edu antje_schaefer@med.unc.edu.; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Charité Universitätsmedizin Berlin, Institute of Pathology, Laboratory of Molecular Tumor Pathology and Systems Biology, Berlin, Germany.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Jan 01; Vol. 82 (1), pp. 90-104. Date of Electronic Publication: 2021 Nov 04.
DOI:	10.1158/0008-5472.CAN-20-4218
Abstrakt:	ECT2 is an activator of RHO GTPases that is essential for cytokinesis. In addition, ECT2 was identified as an oncoprotein when expressed ectopically in NIH/3T3 fibroblasts. However, oncogenic activation of ECT2 resulted from N-terminal truncation, and such truncated ECT2 proteins have not been found in patients with cancer. In this study, we observed elevated expression of full-length ECT2 protein in preneoplastic colon adenomas, driven by increased ECT2 mRNA abundance and associated with APC tumor-suppressor loss. Elevated ECT2 levels were detected in the cytoplasm and nucleus of colorectal cancer tissue, suggesting cytoplasmic mislocalization as one mechanism of early oncogenic ECT2 activation. Importantly, elevated nuclear ECT2 correlated with poorly differentiated tumors, and a low cytoplasmic:nuclear ratio of ECT2 protein correlated with poor patient survival, suggesting that nuclear and cytoplasmic ECT2 play distinct roles in colorectal cancer. Depletion of ECT2 reduced anchorage-independent cancer cell growth and invasion independent of its function in cytokinesis, and loss of Ect2 extended survival in a Kras G12D Apc -null colon cancer mouse model. Expression of ECT2 variants with impaired nuclear localization or guanine nucleotide exchange catalytic activity failed to restore cancer cell growth or invasion, indicating that active, nuclear ECT2 is required to support tumor progression. Nuclear ECT2 promoted ribosomal DNA transcription and ribosome biogenesis in colorectal cancer. These results support a driver role for both cytoplasmic and nuclear ECT2 overexpression in colorectal cancer and emphasize the critical role of precise subcellular localization in dictating ECT2 function in neoplastic cells. SIGNIFICANCE: ECT2 overexpression and mislocalization support its role as a driver in colon cancer that is independent from its function in normal cell cytokinesis. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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