P66shc and its downstream Eps8 and Rac1 proteins are upregulated in esophageal cancers

Abstract

Members of Shc (src homology and collagen homology) family, p46shc, p52shc, p66shc have known to be related to cell proliferation and carcinogenesis. Whereas p46shc and p52shc drive the reaction forward, the role of p66shc in cancers remains to be understood clearly. Hence, their expression in cancers needs to be evaluated carefully so that Shc analysis may provide prognostic information in the development of carcinogenesis. In the present study, the expression of p66shc and its associate targets namely Eps8 (epidermal pathway substrate 8), Rac1 (ras-related C3 botulinum toxin substrate1) and Grb2 (growth factor receptor bound protein 2) were examined in fresh tissue specimens from patients with esophageal squamous cell carcinoma and esophageal adenocarcinoma using western blot analysis. A thorough analysis of both esophageal squamous cell carcinoma and adenocarcinoma showed p66shc expression to be significantly higher in both types of carcinomas as compared to the controls. The controls of adenocarcinoma show a higher basal expression level of p66shc as compared to the controls of squamous cell carcinoma. The expression level of downstream targets of p66shc i.e., eps8 and rac1 was also found to be consistently higher in human esophageal carcinomas, and hence correlated positively with p66shc expression. However the expression of grb2 was found to be equal in both esophageal squamous cell carcinoma and adenocarcinoma. The above results suggest that the pathway operated by p66shc in cancers does not involve the participation of Ras and Grb2 as downstream targets instead it operates the pathway involving Eps8 and Rac1 proteins. From the results it is also suggestive that p66shc may have a role in the regulation of esophageal carcinomas and represents a possible mechanism of signaling for the development of squamous cell carcinoma and adenocarcinoma of esophagus.

Rab25 Is a Tumor Suppressor Gene with Antiangiogenic and Anti-Invasive Activities in Esophageal Squamous Cell Carcinoma

“…And this is also true in the context of ESCCs, as a number of the identified differentially expressed genes involved in integrin signaling in this study (listed in Supplementary Table S4) have already been previously implicated in ESCC pathogenesis. These include CAV1, ROCK1, ITGB1, ICAM1, VCL, PXN, and SHC1 (36)(37)(38)(39)(40)(41)(42)(43)(44). Here, we report the identification and characterization of a tumor suppressor gene Rab25 in ESCCs, which was found to be significantly downregulated in the integrin signaling-associated pathway.…”

Gene expression profiles predictive of outcome and age in infant acute lymphoblastic leukemia: a Children's Oncology Group study

“…EPS8 is an oncoprotein that participates in v-Src-induced cellular transformation, with overexpression enhancing cell proliferation, migration, and tumorigenicity. 37,38 Tumor protein D52 (TPD52) plays a role in Ca 2ϩ -dependent membrane trafficking in proliferating cancer cells and is also a B-cell differentiation marker overexpressed in subsets of pediatric acute leukemia. 39,40 Genes associated with a poorer outcome in this predictor also included human leukocyte antigen class II genes (HLA-DQB1 and multiple HLA-DRB) involved in modulating immune responses.…”

Expression and Clinical Significance of REPS2 in Human Esophageal Squamous Cell Carcinoma

“…We have already mentioned the overexpression of REPS2 may lead to a strong inhibition of Rac1 and Cdc42 signalling that is required for the actin cytoskeleton organization and cell morphogenesis. Rac1 and Cdc42, two members of the Rho family of small GTPases, are all involved in cell transformation, survival, proliferation, invasion and metastasis of human cancer cells (Rincon et al, 2009;Bashir et al, 2010;Feng et al, 2012). Overexpression of Rac1 and Cdc42 have been reported in several types of human cancer including esophageal cancer (Bashir et al, 2010;Feng et al, 2012).…”

“…Rac1 and Cdc42, two members of the Rho family of small GTPases, are all involved in cell transformation, survival, proliferation, invasion and metastasis of human cancer cells (Rincon et al, 2009;Bashir et al, 2010;Feng et al, 2012). Overexpression of Rac1 and Cdc42 have been reported in several types of human cancer including esophageal cancer (Bashir et al, 2010;Feng et al, 2012). Moreover, the latest published report indicated that REPS2 inhibited cell migration by interaction with the paxillin-associated protein PAG2 through its proline-rich motif (Oshiro et al, 2002).…”