Epithelial to Mesenchymal Transition Is Activated in Metastatic Pheochromocytomas and Paragangliomas Caused by SDHB Gene Mutations

Context: Pheochromocytoma and paraganglioma are rare neural-crest-derived tumors. They are metastatic in 15% of cases, and the identification of a germline mutation in the SDHB gene is a predictive risk factor for malignancy and poor prognosis. To date, the link between SDHB mutations and malignancy is still missing. Objective: Epithelial to mesenchymal transition (EMT) is a developmental event, reactivated in cancer cells to promote cell mobility and invasiveness. The aim of this study was to address the participation of EMT in the metastatic evolution of pheochromocytoma/paraganglioma. Design and Patients: Transcriptomic profiling of EMT was performed on 188 tumor samples, using a set of 94 genes implicated in this pathway. Activation of EMT was further confirmed at protein level by immunohistochemistry in a second set of 93 tumors. Results: Hierarchical unsupervised classification showed that most SDHB-metastatic samples clustered together, indicating that EMT is differently regulated in these tumors. Major actors of EMT, metalloproteases and components of cellular junctions, were either up-regulated (LOXL2, TWIST, TCF3, MMP2, and MMP1) or down-regulated (KRT19 and CDH2) in SDHB-metastatic tumors compared with nonmetastatic ones. Interestingly, within metastatic tumors, most of these genes (LOXL2, TWIST, TCF3, MMP2, and KRT19) also allowed us to discriminate SDHB-mutated from non-SDHB-related tumors. In the second set of tumors, we studied Snail1/2 expression by immunohistochemistry and observed its specific nuclear translocation in all SDHB-metastatic tumors. Conclusion: We have identified the first pathway that distinguishes SDHB-metastatic from all other types of pheochromocytomas/paragangliomas and suggest that activation of the EMT process might play a critical role in the particularly invasive phenotype of this group of tumors.

Download Full-text

Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽

10.3390/molecules26113143 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3143

Author(s):

Sergey E. Parfenyev ◽

Sergey V. Shabelnikov ◽

Danila Y. Pozdnyakov ◽

Olga O. Gnedina ◽

Leonid S. Adonin ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Malignant Neoplasm ◽

Malignant Neoplasms ◽

Breast Cancer Patients ◽

Survival Prognosis ◽

Mesenchymal Transition ◽

Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

Download Full-text

The Role of Calcium Signaling in Regulation of Epithelial-Mesenchymal Transition

Cells Tissues Organs ◽

10.1159/000512277 ◽

2020 ◽

pp. 1-23

Author(s):

Divya Adiga ◽

Raghu Radhakrishnan ◽

Sanjiban Chakrabarty ◽

Prashant Kumar ◽

Shama Prasada Kabekkodu

Keyword(s):

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Cancer Therapeutics ◽

Growth And Survival ◽

Mesenchymal Transition ◽

Microenvironmental Factors ◽

Favorable Clinical Outcome

Despite substantial advances in the field of cancer therapeutics, metastasis is a significant challenge for a favorable clinical outcome. Epithelial to mesenchymal transition (EMT) is a process of acquiring increased motility, invasiveness, and therapeutic resistance by cancer cells for their sustained growth and survival. A plethora of intrinsic mechanisms and extrinsic microenvironmental factors drive the process of cancer metastasis. Calcium (Ca2+) signaling plays a critical role in dictating the adaptive metastatic cell behavior comprising of cell migration, invasion, angiogenesis, and intravasation. By modulating EMT, Ca2+ signaling can regulate the complexity and dynamics of events leading to metastasis. This review summarizes the role of Ca2+ signal remodeling in the regulation of EMT and metastasis in cancer.

Download Full-text

USP11 augments TGFβ signalling by deubiquitylating ALK5

Open Biology ◽

10.1098/rsob.120063 ◽

2012 ◽

Vol 2 (6) ◽

pp. 120063 ◽

Cited By ~ 72

Author(s):

Mazin A. Al-Salihi ◽

Lina Herhaus ◽

Thomas Macartney ◽

Gopal P. Sapkota

Keyword(s):

Gene Transcription ◽

Epithelial To Mesenchymal Transition ◽

Nuclear Translocation ◽

Type I ◽

Negative Effects ◽

Transcriptional Responses ◽

Mesenchymal Transition ◽

Tgfβ Receptors ◽

Tgfβ Signalling ◽

Tgfβ Pathway

Summary The TGFβ receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGFβ signals, negatively regulates the TGFβ pathway by recruiting E3 ubiquitin ligases and targeting TGFβ receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGFβ signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGFβ receptor (ALK5), resulting in enhanced TGFβ-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGFβ-induced gene transcription. RNAi -mediated depletion of USP11 results in inhibition of TGFβ-induced SMAD2/3 phosphorylation and TGFβ-mediated transcriptional responses. Central to TGFβ pathway signalling in early embryogenesis and carcinogenesis is TGFβ-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGFβ-induced epithelial to mesenchymal transition.

Download Full-text

Lysyl oxidase promotes epithelial-to-mesenchymal transition during paraquat-induced pulmonary fibrosis

Molecular BioSystems ◽

10.1039/c5mb00698h ◽

2016 ◽

Vol 12 (2) ◽

pp. 499-507 ◽

Cited By ~ 8

Author(s):

Jinfeng Wang ◽

Yong Zhu ◽

Jiuting Tan ◽

Xiaoxiao Meng ◽

Hui Xie ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial To Mesenchymal Transition ◽

Amine Oxidase ◽

Lysyl Oxidase ◽

Critical Role ◽

Mesenchymal Transition

Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in pulmonary fibrosis.

Download Full-text

HSP72 Inhibits Smad3 Activation and Nuclear Translocation in Renal Epithelial-to-Mesenchymal Transition

Journal of the American Society of Nephrology ◽

10.1681/asn.2009050552 ◽

2010 ◽

Vol 21 (4) ◽

pp. 598-609 ◽

Cited By ~ 50

Author(s):

Yi Zhou ◽

Haiping Mao ◽

Shu Li ◽

Shirong Cao ◽

Zhijian Li ◽

...

Keyword(s):

Epithelial To Mesenchymal Transition ◽

Nuclear Translocation ◽

Mesenchymal Transition

Download Full-text

Sip1 mediates an E-cadherin-to-N-cadherin switch during cranial neural crest EMT

The Journal of Cell Biology ◽

10.1083/jcb.201305050 ◽

2013 ◽

Vol 203 (5) ◽

pp. 835-847 ◽

Cited By ~ 91

Author(s):

Crystal D. Rogers ◽

Ankur Saxena ◽

Marianne E. Bronner

Keyword(s):

Neural Crest ◽

Neural Tube ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Critical Role ◽

Embryonic Stem ◽

Neural Crest Cell ◽

Stem Cell Population ◽

Mesenchymal Transition ◽

E Cadherin

The neural crest, an embryonic stem cell population, initially resides within the dorsal neural tube but subsequently undergoes an epithelial-to-mesenchymal transition (EMT) to commence migration. Although neural crest and cancer EMTs are morphologically similar, little is known regarding conservation of their underlying molecular mechanisms. We report that Sip1, which is involved in cancer EMT, plays a critical role in promoting the neural crest cell transition to a mesenchymal state. Sip1 transcripts are expressed in premigratory/migrating crest cells. After Sip1 loss, the neural crest specifier gene FoxD3 was abnormally retained in the dorsal neuroepithelium, whereas Sox10, which is normally required for emigration, was diminished. Subsequently, clumps of adherent neural crest cells remained adjacent to the neural tube and aberrantly expressed E-cadherin while lacking N-cadherin. These findings demonstrate two distinct phases of neural crest EMT, detachment and mesenchymalization, with the latter involving a novel requirement for Sip1 in regulation of cadherin expression during completion of neural crest EMT.

Download Full-text

Extracellular HSP90α-LRP1 Signaling Promote Pancreatic Cancer Metastasis and Chemoresistance Via Regulating Epithelial-To-Mesenchymal Transition

10.21203/rs.3.rs-1088653/v1 ◽

2021 ◽

Author(s):

Nina Xue ◽

Tingting Du ◽

Fangfang Lai ◽

Jing Jin ◽

Ming Ji ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Density Lipoprotein ◽

Underlying Mechanism ◽

Migration And Invasion ◽

Mesenchymal Transition

Abstract Extracellular heat shock protein 90α (HSP90α) has been reported to promote cancer cell invasion and migration. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α and its underlying mechanism for PC progression were still unclear. Our study pointed out that highly invasive Capan2 cells has a higher level of secreted HSP90α, rather than membrane HSP90α, compared with those of less invasive PL45 cells. The conditioned medium of Capan2 cells or recombinant HSP90α protein was able to stimulate the migration and invasion of PL45 or capan2 cells, which could be prevented by a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition (EMT) in PL45 cells, including increases in vimentin and snail expressions, decreases in E-cadherin expression and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by anti-HSP90α antibody in Capan2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) mRNA were associated with worsened patient survival in pancreatic adenocarcinoma. LRP1 as a receptor of eHSP90α for its stimulatory role of PC cells EMT and metastasis by activating AKT signaling. Down-regulation of LRP1 could promote chemosensitivity to gemcitabine and doxorubicin, but not to topotecan and paclitaxel in Capan2 cells. Therefore, our study reveals a critical role of secreted HSP90α on EMT events and suggests blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance.

Download Full-text

ROS Promote Hypoxia-Induced Keratinocyte Epithelial-Mesenchymal Transition by Inducing SOX2 Expression and Subsequent Activation of Wnt/β-Catenin

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/1084006 ◽

2022 ◽

Vol 2022 ◽

pp. 1-23

Author(s):

Yan Shi ◽

Shang Wang ◽

Ronghua Yang ◽

Zhenmin Wang ◽

Weiwei Zhang ◽

...

Keyword(s):

Wound Healing ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Mesenchymal Transition ◽

Sox2 Expression ◽

Subsequent Activation ◽

And Migration

We previously showed that wound-induced hypoxia is related to keratinocyte migration. The ability of keratinocytes within wound healing to undergo epithelial to mesenchymal transition (EMT) contributes significantly to the acquisition of migratory properties. However, the effect of hypoxia on keratinocyte EMT on wound healing and the potential mechanism are poorly documented. This study first demonstrated that reactive oxygen species (ROS) appear to be an essential signalling mediator in keratinocytes with increased EMT and migration subjected to hypoxic conditions. Next, we showed that the expression of sex-determining region Y-box 2 (SOX2), a stemness-associated molecule, is ROS-dependent under hypoxia and that SOX2 inhibition in keratinocytes dramatically prevented hypoxia-induced EMT and migration. In addition, β-catenin was found to be a potential molecular target of SOX2, and the activation of Wnt/β-catenin was required for hypoxia-induced EMT and migration. Using an in vitro skin culture model and an in vivo skin wound model, our study further reinforced the critical role of ROS in inducing EMT through SOX2 expression and subsequent activation of Wnt/β-catenin, allowing for rapid reepithelialization of the wound area. Taken together, our findings reveal a previously unknown mechanism by which hypoxia promotes wound healing by promoting reepithelialization through the production of ROS, inducing keratinocyte EMT and migration via the enhancement of SOX2 and activation of Wnt/β-catenin.

Download Full-text

β-Catenin/Smad3 Interaction Regulates Transforming Growth Factor-β-Induced Epithelial to Mesenchymal Transition in the Lens

International Journal of Molecular Sciences ◽

10.3390/ijms20092078 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2078 ◽

Cited By ~ 6

Author(s):

Aftab Taiyab ◽

Julie Holms ◽

Judith A. West-Mays

Keyword(s):

Growth Factor ◽

Signaling Pathways ◽

Epithelial To Mesenchymal Transition ◽

Vision Loss ◽

Transforming Growth Factor ◽

Nuclear Translocation ◽

Ex Vivo ◽

Smooth Muscle Actin ◽

Posterior Capsular Opacification ◽

Mesenchymal Transition

Cataracts are the leading cause of blindness worldwide. Although surgery is a successful method to restore vision loss due to cataracts, post-surgical complications can occur, such as secondary cataracts, also known as posterior capsular opacification (PCO). PCO arises when lens epithelial cells (LEC) are left behind in the capsular bag following surgery and are induced to undergo epithelial to mesenchymal transition (EMT). Following EMT, LEC morphology and phenotype are altered leading to a loss of transparency and vision. Transforming growth factor (TGF)-β-induced signaling through both canonical, TGF-β/Smad, and non-canonical, β-catenin/Wnt and Rho/ROCK/MRTF-A, pathways have been shown to be involved in lens EMT, and thus PCO. However, the interactions between these signaling pathways in the lens have not been thoroughly explored. In the current study we use rat LEC explants as an ex vivo model, to examine the interplay between three TGF-β-mediated pathways using α-smooth muscle actin (α-SMA) as a molecular marker for EMT. We show that Smad3 inhibition via SIS3 prevents nuclear translocation of β-catenin and MRTF-A, and α-SMA expression, suggesting a key role of Smad3 in regulation of MRTF-A and β-catenin nuclear transport in LECs. Further, we demonstrate that inhibition of β-catenin/CBP interaction by ICG-001 decreased the amount of phosphorylated Smad3 upon TGF-β stimulation in addition to significantly decreasing the expression levels of TGF-β receptors, TBRII and TBRI. Overall, our findings demonstrate interdependence between the canonical and non-canonical TGF-β-mediated signaling pathways controlling EMT in the lens.

Download Full-text

Control of the Epithelial-to-Mesenchymal Transition and Cancer Metastasis by Autophagy-Dependent SNAI1 Degradation

Cells ◽

10.3390/cells8020129 ◽

2019 ◽

Vol 8 (2) ◽

pp. 129 ◽

Cited By ~ 9

Author(s):

Sahib Zada ◽

Jin Hwang ◽

Mahmoud Ahmed ◽

Trang Lai ◽

Trang Pham ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Nuclear Translocation ◽

Degradation Process ◽

Mesenchymal Transition ◽

Invasion And Migration

Autophagy, an intracellular degradation process, is essential for maintaining cell homeostasis by removing damaged organelles and proteins under various conditions of stress. In cancer, autophagy has conflicting functions. It plays a key role in protecting against cancerous transformation by maintaining genomic stability against genotoxic components, leading to cancerous transformation. It can also promote cancer cell survival by supplying minimal amounts of nutrients during cancer progression. However, the molecular mechanisms underlying how autophagy regulates the epithelial-to-mesenchymal transition (EMT) and cancer metastasis are unknown. Here, we show that starvation-induced autophagy promotes Snail (SNAI1) degradation and inhibits EMT and metastasis in cancer cells. Interestingly, SNAI1 proteins were physically associated and colocalized with LC3 and SQSTM1 in cancer cells. We also found a significant decrease in the levels of EMT and metastatic proteins under starvation conditions. Furthermore, ATG7 knockdown inhibited autophagy-induced SNAI1 degradation in the cytoplasm, which was associated with a decrease in SNAI1 nuclear translocation. Moreover, cancer cell invasion and migration were significantly inhibited by starvation-induced autophagy. These findings suggest that autophagy-dependent SNAI1 degradation could specifically regulate EMT and cancer metastasis during tumorigenesis.

Download Full-text