Epithelial-Mesenchymal Transition in Cervical Cancer: Correlation with Tumor Progression, Epidermal Growth Factor Receptor Overexpression, and Snail Up-Regulation

Abstract

Purpose: Acquisition of epithelial-mesenchymal transition (EMT) by primary carcinoma cells is associated with disrupted epithelial integrity, local invasion, and ultimately metastasis. Little is known about the existence and function of EMT in cervical cancer. This study aims to investigate the regulation of EMT in cervical squamous cell carcinoma. Experimental Design: We investigated the molecular events of EMT in surgical specimens, which present the progression of cervical carcinoma.Two cervical cancer cell lines and the primary culture of normal cervical epithelia were used to study the regulatory mechanisms of EMT. Results: The chronic epidermal growth factor (EGF) treatment induces the elongation of cell shape, increases cell scattering, and enhances cell invasion. EGF treatment down-regulates E-cadherin and up-regulates vimentin in cervical cancer cells.These characteristics are consistent with the morphologic changes, molecular events, and functional significance of EMT. EGF receptor (EGFR) signaling inactivates glycogen synthase kinase-3h, which results in the nuclear accumulation of up-regulated Snail and then leads to EMT program. a 5 h 1 integrin signaling and extracellular matrix fibronectin can modulate EGF-induced EMT. Importantly, the immunofluorescent stainings of surgical specimens indicate that cervical carcinoma progression is accompanied by EGFR overexpression, which is in parallel with decreased E-cadherin and increased vimentin. Up-regulation and nuclear accumulation of Snail correlate with EMT program in tumor tissues. Conclusion: EGF cooperates with a 5 h 1 integrin signaling to induce EMT in cervical cancer cells via up-regulated Snail. Blockade of EGFR activity or expression may provide a potential target for the treatment of cervical cancer progression.During metastatic progression, polarized epithelial tumor cells convert into motile mesenchymal cells, invade the basement membrane beneath, enter blood vessels, and disseminate into secondary organ. The initial stage of these processes is associated with morphogenetic changes referred to as epithelial-mesenchymal transition (EMT), which is characterized by morphologic changes from epithelial cells to fibroblast-like cells, disassembly of intercellular junctions, and increased cell motility (1, 2). Down-regulation of E-cadherin was considered as a critical step in EMT process, and the down-regulation of which can be achieved by transcriptional suppression mediated by transcription factors Snail, Slug,. This results in the disruption of intracellular adhesion junctions formed by E-cadherin/h-catenin complexes.Cervical cancer is the second most common cancer among women worldwide (6). A growing body of evidence has accumulated to indicate that oncogenic types of human papillomavirus serve as an important factor in the development of the precursors of cervical cancer. However, only a small fraction of those infected by human papillomavirus develops cancer, indicating that other factors contribute to the progression to cervical can...

Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells

“…More important, we show that inactivation of Akt largely eliminates these EGF-mediated signaling events, suggesting that Akt is a central player in EGFRdirected cell migration. Similar observations have been recently reported in cervical cancer cells (Lee et al, 2008). In addition, we found that knockdown of endogenous Snail in prostate cancer cells significantly interrupts EGF-induced E-cadherin loss, EMT and motility.…”

“…Studies within carcinoma cell lines from disparate epithelial tissues have supplied evidence for several different signaling pathways (b-catenin-TCF/LEF-1, ERK, STAT3), as well as alternate repressors of E-cadherin transcription (Twist, Slug) involved in activation of EMT (Conacci-Sorrell et al, 2003;Lu et al, 2003;Lo et al, 2007), reflective of the fact that cancer cells can use completely distinct pathways under diverse biological contexts. Our work in prostate cancer cells, in addition to the study in cervical cancer cells (Lee et al, 2008), adds yet another mechanistic pathway by which carcinoma cells undergo EMT, specifically an EGF/EGFR-mediated EMT pathway through Akt inhibition of GSK3b, followed by stabilization of Snail and downregulation of E-cadherin (EGFR-Akt-GSK3b-Snail-E-cadherin-EMT). Interestingly, we observed that inhibition of ERK signaling rather boosts EGF-induced Akt activation, subsequently enhancing cell motility ( Figure 5 and Supplementary Figure 4).…”

“…It is widely believed that downregulation of E-cadherin occurs through transcriptional repression mediated by the protein, Snail (Cano et al, 2000;Peinado et al, 2007;Moreno-Bueno et al, 2008). Accumulating evidence indicates that the EGFR family and its downstream signaling pathways (for example, PI3K-Akt and rat sarcoma-MEK-ERK) regulate the expression of Snail (Lee et al, 2008;Qiao et al, 2008;Hipp et al, 2010), suggesting that pharmacological inhibition of these pathways may prevent the loss of E-cadherin function and thereby acquisition of invasive motility.…”

Significance of epithelial growth factor in the epithelial–mesenchymal transition of human gallbladder cancer cells

“…(20) In EMT-type cells, the reduction of the epithelial marker ECD occurs in parallel with the induction of the mesenchymal marker VIM. (21) Epithelial-mesenchymal transition occurs during cancer progression and enhances invasion and metastasis. (20) The present study aimed to clarify the relationship between morphogenesis, EMT, and growth factors in GBC cells.…”

Epithelial–mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy

“…EMT markers have been associated with greater tumor invasion and progression in women with CC 31. In particular, HPV E6 oncoprotein expression induces characteristic changes in EMT 32.…”