Intraepithelial Lymphocytes Suppress Intestinal Tumor Growth by Cell-to-Cell Contact via CD103/E-Cadherin Signal

AbstractHistone deacetylases (HDACs) are involved in tumor progression, and some have been successfully targeted for cancer therapy. The expression of histone deacetylase 4 (HDAC4), a class IIa HDAC, was upregulated in our previous microarray screen. However, the role of HDAC4 dysregulation and mechanisms underlying tumor growth and metastasis in nasopharyngeal carcinoma (NPC) remain elusive. Here, we first confirmed that the HDAC4 levels in primary and metastatic NPC tissues were significantly increased compared with those in normal nasopharyngeal epithelial tissues and found that high HDAC4 expression predicted a poor overall survival (OS) and progression-free survival (PFS). Functionally, HDAC4 accelerated cell cycle G1/S transition and induced the epithelial-to-mesenchymal transition to promote NPC cell proliferation, migration, and invasion in vitro, as well as tumor growth and lung metastasis in vivo. Intriguingly, knockdown of N-CoR abolished the effects of HDAC4 on the invasion and migration abilities of NPC cells. Mechanistically, HDAC3/4 binds to the E-cadherin promoter to repress E-cadherin transcription. We also showed that the HDAC4 inhibitor tasquinimod suppresses tumor growth in NPC. Thus, HDAC4 may be a potential diagnostic marker and therapeutic target in patients with NPC.

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Remodeling the cell surface distribution of membrane proteins during the development of epithelial cell polarity.

The Journal of Cell Biology ◽

10.1083/jcb.116.4.889 ◽

1992 ◽

Vol 116 (4) ◽

pp. 889-899 ◽

Cited By ~ 60

Author(s):

D A Wollner ◽

K A Krzeminski ◽

W J Nelson

Keyword(s):

Epithelial Cell ◽

Membrane Proteins ◽

Cell Surface ◽

Mdck Cells ◽

Apical Cell ◽

Cell Contact ◽

Surface Polarity ◽

Lateral Membrane ◽

E Cadherin ◽

Cell Cell

The development of polarized epithelial cells from unpolarized precursor cells follows induction of cell-cell contacts and requires resorting of proteins into different membrane domains. We show that in MDCK cells the distributions of two membrane proteins, Dg-1 and E-cadherin, become restricted to the basal-lateral membrane domain within 8 h of cell-cell contact. During this time, however, 60-80% of newly synthesized Dg-1 and E-cadherin is delivered directly to the forming apical membrane and then rapidly removed, while the remainder is delivered to the basal-lateral membrane and has a longer residence time. Direct delivery of greater than 95% of these proteins from the Golgi complex to the basal-lateral membrane occurs greater than 48 h later. In contrast, we show that two apical proteins are efficiently delivered and restricted to the apical cell surface within 2 h after cell-cell contact. These results provide insight into mechanisms involved in the development of epithelial cell surface polarity, and the establishment of protein sorting pathways in polarized cells.

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Changes in E-cadherin rigidity sensing regulate cell adhesion

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1618676114 ◽

2017 ◽

Vol 114 (29) ◽

pp. E5835-E5844 ◽

Cited By ~ 34

Author(s):

Caitlin Collins ◽

Aleksandra K. Denisin ◽

Beth L. Pruitt ◽

W. James Nelson

Keyword(s):

Cell Adhesion ◽

Signaling Molecules ◽

Membrane Dynamics ◽

Cell Contact ◽

Adhesion Assay ◽

Cell Periphery ◽

Actin Organization ◽

Rigidity Sensing ◽

E Cadherin ◽

Cell Cell

Mechanical cues are sensed and transduced by cell adhesion complexes to regulate diverse cell behaviors. Extracellular matrix (ECM) rigidity sensing by integrin adhesions has been well studied, but rigidity sensing by cadherins during cell adhesion is largely unexplored. Using mechanically tunable polyacrylamide (PA) gels functionalized with the extracellular domain of E-cadherin (Ecad-Fc), we showed that E-cadherin–dependent epithelial cell adhesion was sensitive to changes in PA gel elastic modulus that produced striking differences in cell morphology, actin organization, and membrane dynamics. Traction force microscopy (TFM) revealed that cells produced the greatest tractions at the cell periphery, where distinct types of actin-based membrane protrusions formed. Cells responded to substrate rigidity by reorganizing the distribution and size of high-traction-stress regions at the cell periphery. Differences in adhesion and protrusion dynamics were mediated by balancing the activities of specific signaling molecules. Cell adhesion to a 30-kPa Ecad-Fc PA gel required Cdc42- and formin-dependent filopodia formation, whereas adhesion to a 60-kPa Ecad-Fc PA gel induced Arp2/3-dependent lamellipodial protrusions. A quantitative 3D cell–cell adhesion assay and live cell imaging of cell–cell contact formation revealed that inhibition of Cdc42, formin, and Arp2/3 activities blocked the initiation, but not the maintenance of established cell–cell adhesions. These results indicate that the same signaling molecules activated by E-cadherin rigidity sensing on PA gels contribute to actin organization and membrane dynamics during cell–cell adhesion. We hypothesize that a transition in the stiffness of E-cadherin homotypic interactions regulates actin and membrane dynamics during initial stages of cell–cell adhesion.

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Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis

Journal of Biological Chemistry ◽

10.1074/jbc.m115.669481 ◽

2015 ◽

Vol 290 (50) ◽

pp. 29781-29793 ◽

Cited By ~ 21

Author(s):

Masaki Inada ◽

Morichika Takita ◽

Satoshi Yokoyama ◽

Kenta Watanabe ◽

Tsukasa Tominari ◽

...

Keyword(s):

Tumor Growth ◽

Prostaglandin E2 ◽

Melanoma Cell ◽

Stromal Cell ◽

Cell Contact ◽

Receptor Signaling ◽

Ep4 Receptor

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Cell-to-cell contact influences proliferative marker expression and apoptosis in MIN6 cells grown in islet-like structures

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00424.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. E502-E509 ◽

Cited By ~ 40

Author(s):

Melanie J. Luther ◽

Emma Davies ◽

Dany Muller ◽

Moira Harrison ◽

Adrian J. Bone ◽

...

Keyword(s):

Cellular Proliferation ◽

Kinase Inhibitors ◽

Three Dimensional ◽

Cell Aggregation ◽

Cell Interactions ◽

Cell Phenotype ◽

Cell Contact ◽

Min6 Cells ◽

Primary Mouse ◽

E Cadherin

Cell-to-cell interactions play an important role in the development and maintenance of the β-cell phenotype. Here, we have investigated whether E-cadherin plays a role in regulating the growth of insulin-secreting MIN6 cells configured as three-dimensional islet-like clusters (pseudoislets). Pseudoislets form by cell aggregation rather than by proliferation from individual cells and attain the size of primary mouse islets after ∼7 days of maintenance in culture. E-cadherin is known to mediate homotypic cell adhesion between β-cells and has also been implicated in a number of cellular processes, including proliferation, apoptosis, and differentiation. E-cadherin and its associated intracellular elements, α- and β-catenin, were upregulated in MIN6 pseudoislets. Pseudoislet formation was associated with an increased expression of cyclin-dependent kinase inhibitors and a concomitant downregulation of Ki67, suggesting an overall reduction in cellular proliferation. However, measurements of 5-bromo-2′-deoxyuridine incorporation revealed that there were no differences in the rate of MIN6 cell proliferation whether they were configured as monolayers or as pseudoislets, which is likely to be a result of their being a transformed cell line. Cells within pseudoislets were not necrotic, but apoptosis appeared to be upregulated in the islet-like structures. However, no differential expression of Fas and FasL was detected in monolayers and pseudoislets. These results suggest that cell-to-cell interactions within islet-like structures may initiate antiproliferative and proapoptotic signals.

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Epithelial-to-mesenchymal transition in cyst lining epithelial cells in an orthologous PCK rat model of autosomal-recessive polycystic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00038.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. F511-F520 ◽

Cited By ~ 30

Author(s):

Hiroko Togawa ◽

Koichi Nakanishi ◽

Hironobu Mukaiyama ◽

Taketsugu Hama ◽

Yuko Shima ◽

...

Keyword(s):

Kidney Disease ◽

Epithelial Cells ◽

Polycystic Kidney Disease ◽

Autosomal Recessive ◽

Epithelial To Mesenchymal Transition ◽

Cell Contact ◽

Polycystic Kidney ◽

Mesenchymal Transition ◽

Cyst Lining ◽

E Cadherin

In polycystic kidney disease (PKD), cyst lining cells show polarity abnormalities. Recent studies have demonstrated loss of cell contact in cyst cells, suggesting induction of epithelial-to-mesenchymal transition (EMT). Recently, EMT has been implicated in the pathogenesis of PKD. To explore further evidence of EMT in PKD, we examined age- and segment-specific expression of adhesion molecules and mesenchymal markers in PCK rats, an orthologous model of human autosomal-recessive PKD. Kidneys from 5 male PCK and 5 control rats each at 0 days, 1, 3, 10, and 14 wk, and 4 mo of age were serially sectioned and stained with segment-specific markers and antibodies against E-cadherin, Snail1, β-catenin, and N-cadherin. mRNAs for E-cadherin and Snail1 were quantified by real-time PCR. Vimentin, fibronectin, and α-smooth muscle actin (α-SMA) expressions were assessed as mesenchymal markers. E-cadherin expression pattern was correlated with the disease pathology in that tubule segments showing the highest expression in control had much severer cyst formation in PCK rats. In PCK rats, E-cadherin and β-catenin in cystic tubules was attenuated and localized to lateral areas of cell-cell contact, whereas nuclear expression of Snail1 increased in parallel with cyst enlargement. Some epithelial cells in large cysts derived from these segments, especially in adjacent fibrotic areas, showed positive immunoreactivity for vimentin and fibronectin. In conclusion, these findings suggest that epithelial cells in cysts acquire mesenchymal features in response to cyst enlargement and participate in progressive renal fibrosis. Our study clarified the nephron segment-specific cyst profile related to EMT in PCK rats. EMT may play a key role in polycystic kidney disease.

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