Abstract P5-04-03: Aggressiveness of epithelial cancers is independent of epithelial-to-mesenchymal transition

Malic enzyme 1 (ME1) is a cytosolic protein that catalyzes the conversion of malate to pyruvate while concomitantly generating NADPH from NADP. Early studies identified ME1 as a mediator of intermediary metabolism primarily through its participatory roles in lipid and cholesterol biosynthesis. ME1 was one of the first identified insulin-regulated genes in liver and adipose and is a transcriptional target of thyroxine. Multiple studies have since documented that ME1 is pro-oncogenic in numerous epithelial cancers. In tumor cells, the reduction of ME1 gene expression or the inhibition of its activity resulted in decreases in proliferation, epithelial-to-mesenchymal transition and in vitro migration, and conversely, in promotion of oxidative stress, apoptosis and/or cellular senescence. Here, we integrate recent findings to highlight ME1’s role in oncogenesis, provide a rationale for its nexus with metabolic syndrome and diabetes, and raise the prospects of targeting the cytosolic NADPH network to improve therapeutic approaches against multiple cancers.

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Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?

Cancers ◽

10.3390/cancers13071736 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1736

Author(s):

Iuliu Sbiera ◽

Stefan Kircher ◽

Barbara Altieri ◽

Martin Fassnacht ◽

Matthias Kroiss ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Clinical Markers ◽

Positive Role ◽

Tissue Samples ◽

Mesenchymal Transition ◽

Epithelial Markers ◽

Epithelial Cancers ◽

Adrenocortical Adenomas ◽

Slug Expression ◽

The Impact

A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.

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The miR-200 Family of microRNAs: Fine Tuners of Epithelial-Mesenchymal Transition and Circulating Cancer Biomarkers

Cancers ◽

10.3390/cancers13235874 ◽

2021 ◽

Vol 13 (23) ◽

pp. 5874

Author(s):

Ilaria Cavallari ◽

Francesco Ciccarese ◽

Evgeniya Sharova ◽

Loredana Urso ◽

Vittoria Raimondi ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Family Members ◽

Chromosome 1 ◽

Mesenchymal Transition ◽

Epithelial Cancers ◽

Evolutionarily Conserved ◽

Epithelial Phenotype ◽

Human Chromosome 1

The miR-200 family of microRNAs (miRNAs) includes miR-200a, miR-200b, miR-200c, miR-141 and miR-429, five evolutionarily conserved miRNAs that are encoded in two clusters of hairpin precursors located on human chromosome 1 (miR-200b, miR-200a and miR-429) and chromosome 12 (miR-200c and miR-141). The mature -3p products of the precursors are abundantly expressed in epithelial cells, where they contribute to maintaining the epithelial phenotype by repressing expression of factors that favor the process of epithelial-to-mesenchymal transition (EMT), a key hallmark of oncogenic transformation. Extensive studies of the expression and interactions of these miRNAs with cell signaling pathways indicate that they can exert both tumor suppressor- and pro-metastatic functions, and may serve as biomarkers of epithelial cancers. This review provides a summary of the role of miR-200 family members in EMT, factors that regulate their expression, and important targets for miR-200-mediated repression that are involved in EMT. The second part of the review discusses the potential utility of circulating miR-200 family members as diagnostic/prognostic biomarkers for breast, colorectal, lung, ovarian, prostate and bladder cancers.

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Cadherin Expression and EMT: A Focus on Gliomas

Biomedicines ◽

10.3390/biomedicines9101328 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1328

Author(s):

Carolina Noronha ◽

Ana Sofia Ribeiro ◽

Ricardo Taipa ◽

Diogo S. Castro ◽

Joaquim Reis ◽

...

Keyword(s):

Cell Adhesion ◽

Calcium Binding ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Potential Contribution ◽

Epithelial Tumor ◽

Mesenchymal Transition ◽

Epithelial Cancers ◽

Tumor Invasiveness ◽

Cell Adhesion And Migration

Cadherins are calcium-binding proteins with a pivotal role in cell adhesion and tissue homeostasis. The cadherin-dependent mechanisms of cell adhesion and migration are exploited by cancer cells, contributing to tumor invasiveness and dissemination. In particular, cadherin switch is a hallmark of epithelial to mesenchymal transition, a complex development process vastly described in the progression of most epithelial cancers. This is characterized by drastic changes in cell polarity, adhesion, and motility, which lead from an E-cadherin positive differentiated epithelial state into a dedifferentiated mesenchymal-like state, prone to metastization and defined by N-cadherin expression. Although vastly explored in epithelial cancers, how these mechanisms contribute to the pathogenesis of other non-epithelial tumor types is poorly understood. Herein, the current knowledge on cadherin expression in normal development in parallel to tumor pathogenesis is reviewed, focusing on epithelial to mesenchymal transition. Emphasis is taken in the unascertained cadherin expression in CNS tumors, particularly in gliomas, where the potential contribution of an epithelial-to-mesenchymal-like process to glioma genesis and how this may be associated with changes in cadherin expression is discussed.

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The role of DUBs in the post-translational control of cell migration

Essays in Biochemistry ◽

10.1042/ebc20190022 ◽

2019 ◽

Vol 63 (5) ◽

pp. 579-594 ◽

Cited By ~ 2

Author(s):

Guillem Lambies ◽

Antonio García de Herreros ◽

Víctor M. Díaz

Keyword(s):

Cell Migration ◽

Translational Control ◽

Epithelial To Mesenchymal Transition ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Mesenchymal Transition ◽

Tgfβ Receptors ◽

Fundamental Process ◽

Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

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