Clinical Significance of Epithelial-Mesenchymal Transition-Associated Markers in Malignant Pleural Mesothelioma

Abstract

Epithelioid tumors with aggressive behavior have been reported; however, the epithelioid type of malignant pleural mesothelioma (MPM) has a less aggressive behavior. Few studies have evaluated the prognostic value of epithelial-mesenchymal transition (EMT) markers in MPM. We hypothesized that mesenchymal characteristics might predominate in the tumors. Tumor specimens were collected from 33 consecutive patients. We analyzed the EMT expression levels in tumor samples by an immunohistochemical analysis. Positive expression of E-cadherin, γ-catenin, vimentin, fibronectin, Twist and YB-1 was observed in 25, 14, 21, 1, 19 and 18 patients, respectively. No significant association between these markers and the clinicopathological characteristics was found. γ-Catenin demonstrated a trend towards decreased expression in sarcomatoid tumors compared to epithelioid tumors. On the other hand, a trend was noted towards higher expression of vimentin, Twist and YB-1 in sarcomatoid tumors. The survival curves demonstrated that the patients with negative γ-catenin and positive Twist staining had a tendency to have a worse prognosis. Although the individual proteins might not significantly affect the progression of MPM, the combination of γ-catenin and Twist staining can predict the prognosis of patients with MPM.

Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma

“…40,41 YBX1 and its positive regulator twist family bHLH transcription factor 1 are expressed highly in sarcomatoid MPM, and both are linked to epithelial-mesenchymal transition. 42 Here, YBX1 was required for the proliferation of some cell lines and was essential in the colony-forming ability, migration, and invasion of all MPM cells tested, which is consistent with its role in the invasion and migration of other cancer cell types. 39 Taken together, our results show that YBX1 is an important target of miR-137, particularly as it is so integrally involved in invasion and migration of MPM, a malignancy characterized by aggressive local invasion.…”

“…43 In addition to miRNAs, twist family bHLH transcription factor 1 directly targets and enhances YB1 expression and is differentially expressed in sarcomatoid versus nonsarcomatoid MPM. 42,44 The application of effective miRNA-and siRNA-based therapies is becoming feasible thanks to the development of novel miRNA delivery methods, such as EnGeneIC Dream Vector nanocells (EDVs). 45 We have performed several preclinical studies utilizing EDVs in MPM 26,27 and have completed a phase I clinical trial with intravenously administered miRNA-loaded EDVs.…”

Epigenetic down‐regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma

“…In contrast to normal mesothelial cells, MPM cells acquire a highly motile phenotype and the capacity to form multiple tumour nodules with an abundant stromal component. The molecular background of this transition is one of the key questions in MPM research . Since cell migration has a key role during MPM progression , we aimed to identify genes that might be involved in the regulation of MPM cell motility.…”

Establishing a panel of chemo-resistant mesothelioma models for investigating chemo-resistance and identifying new treatments for mesothelioma

“…The role of epithelial to mesenchymal transition (EMT) in the morphology of MM is uncertain35. Therefore, we assessed the levels of two well-known EMT markers E-cadherin and vimentin, as well as the proliferative marker Ki67 in the tumors.…”