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Introduction
The ubiquitin-proteasome pathway is involved in tumorigenesis (1). E2-EPF is a 24-kDa protein that is a member of the E2 family of ubiquitin-conjugating enzymes (2), which, together with an E1 ubiquitin-activating enzyme and an E3 ubiquitin ligase, catalyze the addition of ubiquitin to substrate proteins (3). Multiple rounds of ubiquitinylation result in substrate polyubiquitinylation that can target proteins for proteasome-dependent destruction. E2-EPF was discovered in 1992 and was highly expressed in human cancer tissues compared with normal tissues (4,5). Large-scale meta-analysis of cancer microarray data identifies that E2-EPF is one of commonly activated genes in multiple cancer (6). Though discovered in 1992, candidate substrates and cognate E3 ligases for E2-EPF were unclear until Jung et al demonstrated that the stability of a von Hippel-Lindau (VHL) tumorsuppressor gene product is dependent on E2-EPF levels in 2006 (7). As we know, human solid tumors contain hypoxic regions that have considerably lower oxygen tension than normal tissues. Hypoxia offers resistance to radiotherapy and anticancer chemotherapy, as well as predispose to increased tumor metastases. Furthermore, hypoxia induces hypoxia inducible factor (HIF)-1, which in turn increases tumor angiogenesis (8). The von Hippel-Lindau tumor suppressor, pVHL, forms part of an E3 ubiquitin ligase complex that targets specific substrates for degradation, including HIF-1α (9). Their study suggested a role for E2-EPF in the stabilization of HIF-1α by specifically targeting pVHL for degradation under normoxic conditions. E2-EPF expression level correlates inversely with pVHL level in most tumor cell lines. In vitro and in vivo, forced expression of E2-EPF boosts tumor-cell proliferation, invasion and metastasis through effects on the pVHL-HIF pathway (7).
Thereafter, increased expression of E2-EPF expression in multiple cancers including breast cancer (10) and esophageal squamous cell carcinoma (11) was reported and their roles in tumor cell growth and metastasis were explored. Cellular factors that regulate the expression of E2-EPF gene were also revealed. Growth factors and serum induce expression of Egr-1 and SRF, respectively. Egr-1 and SRF can bind the promotor region of E2-EPF, therefore increase the HIF-1α protein level under non-hypoxic conditions through the Egr-1/SRF- E2-EPF-VHL pathway (12).
Here, we report the expression profile for E2-EPF in cervical tumor and normal tissue specimens and address that it has an essential role in cancer cell proliferation, invasion, tumorigenicity and...