Note | |
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Entity | Human cancer |
Note | The ECT2 gene was initially identified as a proto-oncogene capable of transforming NIH/3T3 fibroblasts (Miki et al., 1993). Subsequent analysis revealed that the originally characterized oncogenic Ect2 clone actually consisted of a carboxyl-terminal truncation of the full-length ECT2 gene. This truncated clone encoded a protein consisting of the DH-PH-C domains of Ect2. This mutant localized to the cytoplasm, possessed constitutive GEF activity and could transform fibroblasts in vitro (Saito et al., 2004). Expression analysis revealed that established human cancer cell lines express only full-length Ect2, indicating that the transforming C-terminal Ect2 fragment originally cloned is not directly relevant to cancer biology (Saito et al., 2003). Interestingly, full length Ect2 is overexpressed in several human tumor types, suggesting a role for elevated Ect2 expression in these tumors (Hirata et al., 2009; Salhia et al., 2008; Sano et al., 2006; Zhang et al., 2008). |
Prognosis | Ect2 overexpression is associated with poor prognosis in patients with non-small cell lung cancer (NSCLC), esophageal squamous cell carcinomas (ESCC) (Hirata et al., 2009), glioblastoma multiforme (GBM) (Salhia et al., 2008; Sano et al., 2006) and oral squamous cell carcinomas (OSCC) (Iyoda et al., 2010). |
Cytogenetics | ECT2 is amplified as part of the 3q26 amplicon a region frequently targeted for chromosomal alterations in human tumors (Eder et al., 2005; Han et al., 2002; Lin et al., 2006; Zhang et al., 2006). ECT2 amplification frequently occurs in lung squamous cell carcinomas (LSCC) (Justilien and Fields, 2009), ESCC (Yang et al., 2008; Yen et al., 2005) and cervical cancer (Vazquez-Mena et al., 2012). |
Oncogenesis | Ect2 is overexpressed and mislocalized in human tumors Ect2 is highly expressed in a variety of human tumors including brain (Salhia et al., 2008; Sano et al., 2006), lung (Hirata et al., 2009; Justilien and Fields, 2009), bladder (Saito et al., 2004), esophageal (Hirata et al., 2009), pancreatic (Zhang et al., 2008), cervical (Vazquez-Mena et al., 2012), colorectal (Jung et al., 2011), oral (Iyoda et al., 2010) and ovarian tumors (Saito et al., 2004). Tumor specific ECT2 gene amplification drives Ect2 overexpression in lung (Hirata et al., 2009; Justilien and Fields, 2009), esophageal (Hirata et al., 2009) and cervical cancers (Vazquez-Mena et al., 2012). Ect2 transforming activity requires both Ect2 GEF activity and mis-localization of Ect2 to the cytoplasm (Saito et al., 2004; Solski et al., 2004). Immunohistochemical analysis demonstrate that Ect2 is predominantly expressed in the nucleus of normal lung epithelial cells (Justilien and Fields, 2009), but that primary NSCLC tumors display increased Ect2 staining in both the nucleus and cytoplasm with little or no staining in the tumor-associated stroma (Hirata et al., 2009; Justilien and Fields, 2009). Similarly, Ect2 stains primarily nuclear in the low-grade astrocytomas (LGA) whereas glioblastoma multiforme (GBMs) display prominent staining of Ect2 in both the cytoplasm and nucleus (Salhia et al., 2008). OSCCs exhibit strong nuclear and cytoplasmic staining of ECT2 staining whereas normal oral tissues showed little to no ECT2 staining (Iyoda et al., 2010). Ect2 is important for transformation in human cancer cells Ect2 plays a promotive role in transformation in all tumor model systems examined to date. Inhibition of Ect2 expression by RNAi decreases the proliferation of NSCLC (Hirata et al., 2009), ESCC (Hirata et al., 2009) and OSCC (Iyoda et al., 2010) cells in vitro. In addition, stable knockdown (KD) of Ect2 by short hairpin RNAs (shRNAs) inhibits anchorage-independent growth and cellular invasion of multiple NSCLC cell lines (Justilien and Fields, 2009) Ect2 KD impairs tumor growth of NSCLC cells injected into the flanks of athymic nude mice, demonstrating that Ect2 also plays a role in NSCLC tumorigenicity in vivo (Justilien and Fields, 2009). RNAi-mediated suppression of Ect2 expression in glioblastoma cells caused a significant decrease in cell proliferation and migration in vitro and invasion in an ex vivo rat brain slice assay (Salhia et al., 2008; Sano et al., 2006). Cellular mechanisms in Ect2 mediated transformation Ect2 function in NSCLC transformation is distinct from its well established role in cytokinesis. NSCLC cells stably transduced with Ect2 shRNAs do not show significant changes in population doubling time (PDT) or accumulation of multinucleated cells in vitro or in vivo (Justilien and Fields, 2009). NSCLC cells may employ an Ect2-independent cytokinesis mechanism such as previously described in HT1080 fibrosarcoma (Kanada et al., 2008). Whereas Ect2 mediates RhoA activity in cytokinesis, Rac1 appears to be the critical Ect2 effector in NSCLC. Ect2 KD in NSCLC cells leads to a significant decrease in Rac1 activity but no apparent changes in Cdc42 or RhoA activity (Justilien and Fields, 2009; Justilien et al., 2011). Furthermore, expression of a constitutively active Rac1 allele (RacV12) restores anchorage independent growth and invasion in Ect2 KD cells. Co-immunoprecipitation experiments and mass spectrometry analysis show that Ect2 associates with the PKCι-Par6α complex (Justilien and Fields, 2009; Justilien et al., 2011). Ect2 is largely mis-localized to the cytoplasm of cultured NSCLC cells and the PKCι-Par6α complex regulates Ect2 cytoplasmic mislocalization (Justilien and Fields, 2009). Ect2 isolated from NSCLC cells is highly phosphorylated at a novel, previously uncharacterized site T328. PKCι directly phosphorylates T328 in vitro and the PKCι/Par6 complex regulates T328 phosphorylation in intact NSCLC cells. T328 phosphorylation is required for ECT2 binding to the PKCι-Par6 complex, Rac1 activation and transformation in NSCLC cells (Justilien et al., 2011). |
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Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. |
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PMID 12476413 |
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Involvement of epithelial cell transforming sequence-2 oncoantigen in lung and esophageal cancer progression. |
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PMID 19118053 |
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PMID 21124766 |
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Clin Cancer Res. 2011 Feb 15;17(4):700-9. Epub 2011 Feb 8. |
PMID 21304002 |
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PMID 21189248 |
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Accumulation of GTP-bound RhoA during cytokinesis and a critical role of ECT2 in this accumulation. |
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PMID 10837491 |
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DNA copy number gains in head and neck squamous cell carcinoma. |
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PMID 16247453 |
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Nucleotide exchange factor ECT2 interacts with the polarity protein complex Par6/Par3/protein kinase Czeta (PKCzeta) and regulates PKCzeta activity. |
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PMID 15254234 |
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Oncogene ect2 is related to regulators of small GTP-binding proteins. |
Miki T, Smith CL, Long JE, Eva A, Fleming TP. |
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PMID 8464478 |
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Centralspindlin regulates ECT2 and RhoA accumulation at the equatorial cortex during cytokinesis. |
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J Cell Sci. 2006 Jan 1;119(Pt 1):104-14. Epub 2005 Dec 13. |
PMID 16352658 |
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Ect2 and MgcRacGAP regulate the activation and function of Cdc42 in mitosis. |
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J Cell Biol. 2005 Jan 17;168(2):221-32. Epub 2005 Jan 10. |
PMID 15642749 |
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Deregulation and mislocalization of the cytokinesis regulator ECT2 activate the Rho signaling pathways leading to malignant transformation. |
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J Biol Chem. 2004 Feb 20;279(8):7169-79. Epub 2003 Nov 25. |
PMID 14645260 |
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Rho exchange factor ECT2 is induced by growth factors and regulates cytokinesis through the N-terminal cell cycle regulator-related domains. |
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J Cell Biochem. 2003 Nov 1;90(4):819-36. |
PMID 14587037 |
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The guanine nucleotide exchange factors trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma. |
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Am J Pathol. 2008 Dec;173(6):1828-38. Epub 2008 Nov 13. |
PMID 19008376 |
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Expression level of ECT2 proto-oncogene correlates with prognosis in glioma patients. |
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PMID 17016598 |
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PMID 15073184 |
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PMID 14624449 |
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Ect2, an ortholog of Drosophila Pebble, regulates formation of growth cones in primary cortical neurons. |
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PMID 22366651 |
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Amplified genes may be overexpressed, unchanged, or downregulated in cervical cancer cell lines. |
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PMID 12376551 |
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Amplification of PRKCI, located in 3q26, is associated with lymph node metastasis in esophageal squamous cell carcinoma. |
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PMID 17990328 |
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World J Gastroenterol. 2005 Mar 7;11(9):1267-72. |
PMID 15761962 |
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An ECT2-centralspindlin complex regulates the localization and function of RhoA. |
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J Cell Biol. 2005 Aug 15;170(4):571-82. |
PMID 16103226 |
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Integrative genomic analysis of protein kinase C (PKC) family identifies PKCiota as a biomarker and potential oncogene in ovarian carcinoma. |
Zhang L, Huang J, Yang N, Liang S, Barchetti A, Giannakakis A, Cadungog MG, O'Brien-Jenkins A, Massobrio M, Roby KF, Katsaros D, Gimotty P, Butzow R, Weber BL, Coukos G. |
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PMID 16651413 |
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Correlation between ECT2 gene expression and methylation change of ECT2 promoter region in pancreatic cancer. |
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Hepatobiliary Pancreat Dis Int. 2008 Oct;7(5):533-8. |
PMID 18842503 |
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