p120 Catenin-Mediated Stabilization of E-Cadherin Is Essential for Primitive Endoderm Specification.

E-cadherin-mediated cell-cell adhesion is critical for naive pluripotency of cultured mouse embryonic stem cells (mESCs). E-cadherin-depleted mESC fail to downregulate their pluripotency program and are unable to initiate lineage commitment. To further explore the roles of cell adhesion molecules during mESC differentiation, we focused on p120 catenin (p120ctn). Although one key function of p120ctn is to stabilize and regulate cadherin-mediated cell-cell adhesion, it has many additional functions, including regulation of transcription and Rho GTPase activity. Here, we investigated the role of mouse p120ctn in early embryogenesis, mESC pluripotency and early fate determination. In contrast to the E-cadherin-null phenotype, p120ctn-null mESCs remained pluripotent, but their in vitro differentiation was incomplete. In particular, they failed to form cystic embryoid bodies and showed defects in primitive endoderm formation. To pinpoint the underlying mechanism, we undertook a structure-function approach. Rescue of p120ctn-null mESCs with different p120ctn wild-type and mutant expression constructs revealed that the long N-terminal domain of p120ctn and its regulatory domain for RhoA were dispensable, whereas its armadillo domain and interaction with E-cadherin were crucial for primitive endoderm formation. We conclude that p120ctn is not only an adaptor and regulator of E-cadherin, but is also indispensable for proper lineage commitment.

P120-Catenin Mediates Intermittent Cyclic Mechanical Tension-Induced Inflammation in Chondrocytes.

To study the role of the nuclear factor (NF)-κB signaling pathway and P120-catenin in the inflammatory effects of intermittent cyclic mechanical tension (ICMT) on endplate chondrocytes. Inflammatory reactions of endplate chondrocyte were measured by real-time reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assays, a dual-luciferase reporter assay system, immunofluorescence, and Western blot analysis. ICMT loading led to inflammatory reactions of endplate chondrocytes in both the rabbit endplate cartilage model and rat endplate chondrocytes in vitro. Inhibition of NF-κB signaling significantly ameliorated the inflammation induced by ICMT in endplate chondrocytes. Moreover, the expression of P120-catenin was decreased by ICMT. However, over-expression of P120-catenin suppressed NF-κB signaling and reversed the inflammatory effects. P120-catenin prevents endplate chondrocytes from undergoing ICMT-mediated inflammation by suppressing the expression of NF-κB. J. Cell. Biochem. 118: 4508-4516, 2017. © 2017 Wiley Periodicals, Inc.

[Epithelial cadherins and associated molecules in invasive lobular breast cancer]. / Epitelial'nye kadgeriny i assotsiirovannye s nimi molekuly pri invazivnom dol'kovom rake molochnoi zhelezy.

AIM: to estimate the expression of cell adhesion molecules E- and P-cadherin, as well as that of cadherin-catenin complexes in invasive lobular breast cancer (BC) cells. MATERIAL AND METHODS: 250 cases of postoperative material from patients diagnosed with invasive lobular BC were studied. The expressions of cell adhesion molecules E-cadherin, P-cadherin, ß-catenin, p120 catenin, and vimentin were determined by immunohistochemical assay in all cases. The examined cases were divided into molecular biological subtypes, based on the evaluation of estrogen receptors (ER), progesterone receptors (PR), HER-2/neu, and Ki-67 proliferative index. RESULTS: The membrane expression of E-cadherin on the tumor cells was found to be preserved in 93%; the cytoplasmic expression of ß-catenin and p120-catenin appeared in 60 and 72% of cases, respectively. The expression of P-cadherin was detected in 82% of cases. The coexpression of E- and P-cadherin was noted in 90% of all the examined cases. There was a correlation between the expression of E- and P-cadherins (V=0.34; p<0.05). CONCLUSION: The BC cells showed the coexpression of E- and P-cadherins, as well as release of the molecules ß- and p120-catenins into the cytoplasm of tumor cells, which leads to the activation of intracellular mechanisms for changing the structure of the cytoskeleton and the level of proliferation. The above-mentioned mechanisms are accompanied by the activation of epithelial-mesenchymal transition. The intracellular mechanisms resulted in progressive cancer and its metastasis.

Differential role for p120-catenin in regulation of TLR4 signaling in macrophages.

Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-ß-dependent IFN regulatory factor 3 activation and release of IFN-ß upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-ß signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.

δ-catenin promotes the malignant phenotype in breast cancer.

δ-Catenin is a member of the p120 catenin family. Similar to p120ctn, δ-catenin contains nine central Armadillo repeats and binds to the juxtamembrane domain (JMD) of E-cadherin. We used immunohistochemistry to detect δ-catenin expression in breast carcinoma (128 cases), and δ-catenin mRNA and protein expression was detected by reverse transcription-polymerase chain reaction and Western blotting (45 cases). The effects of δ-catenin on the activity of small GTPases and the biological behavior of breast cancer cells were explored by pulldown, flow cytometry, methyl thiazolyl tetrazolium, and Matrigel invasion assays. The results showed that δ-catenin expression increased in breast cancer tissues and was associated with a higher degree of malignancy (invasive lobular breast cancer, high tumor-node-metastasis stage, lymph node metastasis, and C-erbB-2+) and poor prognosis. Postoperative survival was shorter in patients with δ-catenin-positive expression than in patients with negative expression. δ-Catenin may regulate Cdc42/Rac1 activity, promote proliferation and invasion of breast cancer cells, and alter cell cycle progression. We conclude that δ-catenin tends to overexpress in breast carcinoma and promotes the malignant phenotype.

C6orf106 enhances NSCLC cell invasion by upregulating vimentin, and downregulating E-cadherin and P120ctn.

Chromosome 6 open reading frame 106 (C6orf106) is a newly discovered protein; its expression and clinical pathological significance in human tumors remains unclear. Immunohistochemistry, Western blot, and immunofluorescence were performed to assess C6orf106 expression in non-small cell lung cancer (NSCLC). In addition, the relationships between subcellular localization and clinical pathological factors were analyzed. Through C6orf106 overexpression and repression, respectively, in lung cancer cell lines, we explored the effect of this molecule on NSCLC invasion abilities. C6orf106 was highly expressed in the cytoplasm of lung cancer tissue cells (60.4 %, 75/124), compared with adjacent normal lung tissues (15.2 %, 7/46, p < 0.001). In addition, its expression was positively correlated with differentiation (p = 0.001), TNM stage (p = 0.011), lymph node metastasis (p = 0.018), and poor prognosis (p = 0.006). Furthermore, C6orf106 overexpression enhanced NSCLC cell invasion. Moreover, C6orf106 was shown to increase vimentin expression, while decreasing E-cadherin and P120ctn. C6orf106 is highly expressed in NSCLC and correlates with clinical and pathological factors, as well as poor prognosis. C6orf106 promotes invasion in NSCLC cells. Finally, C6orf106 upregulates vimentin, and downregulates E-cadherin and P120ctn.

Protective role of p120-catenin in maintaining the integrity of adherens and tight junctions in ventilator-induced lung injury.

BACKGROUND: Ventilator-induced lung injury (VILI) is one of the most common complications for patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Although p120 is an important protein in the regulation of cell junctions, further mechanisms should be explored for prevention and treatment of VILI. METHODS: Mouse lung epithelial cells (MLE-12), which were transfected with p120 small interfering (si)RNA, p120 cDNA, wild-type E-cadherin juxtamembrane domain or a K83R mutant juxtamembrane domain (K83R-JMD), were subjected to 20% cyclic stretches for 2 or 4 h. Furthermore, MLE-12 cells and mice, which were pretreated with the c-Src inhibitor PP2 or RhoA inhibitor Y27632, underwent 20% cyclic stretches or mechanical stretching, respectively. Moreover, wild-type C57BL/6 mice were transfected with p120 siRNA-liposome complexes before mechanical ventilation. Cell lysates and lung tissues were then analyzed to detect lung injury. RESULTS: cyclic stretches of 20% actived c-Src, which induced degradation of E-cadherin, p120 and occludin. However, loss of p120 increased the degradation and endocytosis of E-cadherin. Immunoprecipitation and Immunofluorescence results showed a decrease in the association between p120 and E-cadherin, while gap formation increased in p120 siRNA and K83R-JMD groups after 20% cyclic stretches. Loss of p120 also reduced the occludin level and decreased the association of occludin and ZO-1 by enhancing RhoA activity. However, the altered levels of occludin and E-cadherin were reversed by PP2 or Y27632 treatments compared with the cyclic stretch group. Consistently, the expression, redistribution and disassociation of junction proteins were all restored in the p120 overexpression group after 20% cyclic stretches. Moreover, the role of p120 in VILI was confirmed by increased wet/dry weigh ratio and enhanced production of cytokines (tumor necrosis factor-α and interleukin-six) in p120-depleted mice under mechanical ventilation. CONCLUSIONS: p120 protected against VILI by regulating both adherens and tight junctions. p120 inhibited E-cadherin endocytosis by increasing the association between p120 and juxtamembrane domain of E-cadherin. Furthermore, p120 reduced the degradation of occludin by inhibiting RhoA activity. These findings illustrated further mechanisms of p120 in the prevention of VILI, especially for patients with ALI or ARDS.

Mono-(2-ethylhexyl) phthalate (MEHP) promotes invasion and migration of human testicular embryonal carcinoma cells.

Testicular dysgenesis syndrome refers to a collection of diseases in men, including testicular cancer, that arise as a result of abnormal testicular development. Phthalates are a class of chemicals used widely in the production of plastic products and other consumer goods. Unfortunately, phthalate exposure has been linked to reproductive dysfunction and has been shown to adversely affect normal germ cell development. In this study, we show that mono-(2-ethylhexyl) phthalate (MEHP) induces matrix metalloproteinase 2 (MMP2) expression in testicular embryonal carcinoma NT2/D1 cells but has no significant effect on MMP9 expression. NT2/D1 cells also have higher levels of MYC expression following MEHP treatment. It is widely recognized that activation of MMP2 and MYC is tightly associated with tumor metastasis and tumor progression. Gelatin zymographic analysis indicates that MEHP strongly activates MMP2 in NT2/D1 cells. Addition of the MMP2-specific inhibitor SB-3CT inhibited MEHP-enhanced cell invasion and migration, demonstrating that MMP2 plays a functional role in promoting testicular embryonal carcinoma progression in response to MEHP exposure. Furthermore, we investigated genome-wide gene expression profiles of NT2/D1 cells following MEHP exposure at 0, 3, and 24 h. Microarray analysis and semiquantitative RT-PCR revealed that MEHP exposure primarily influenced genes in cell adhesion and transcription in NT2/D1 cells. Gap junction protein-alpha 1, vinculin, and inhibitor of DNA-binding protein-1 were significantly down-regulated by MEHP treatment, while claudin-6 and beta 1-catenin expression levels were up-regulated. This study provides insight into mechanisms that may account for modulating testicular cancer progression following phthalate exposure.

Invasive plasmacytoid urothelial carcinoma: A comparative study of E-cadherin and P120 catenin.

Invasive plasmacytoid urothelial carcinomas (PUCs) are an uncommon aggressive variant, which often shows immunohistochemical loss of E-cadherin, underlying its distinct discohesive histology. The marker P120 (well described in breast pathology as being a diagnostic tool alongside E-cadherin for lobular neoplasia) has not been evaluated in PUCs. Biopsies, transurethral resections, and cystectomies of PUCs were collected, and whole-slide immunohistochemical analysis of E-cadherin and P120 was applied. A subset of cases were also tested for CDH1 mutation. PUC cases were stratified into morphologic categories of classic, pleomorphic, or desmoplastic. For E-cadherin, 24 of 33 (73%) cases showed an abnormal staining pattern, consisting of complete absence of staining (17/24; 71%) or cytoplasmic staining (7/24; 29%). For P120, 24 of 33 (73%) cases showed an abnormal staining pattern, consisting of loss of membranous staining with cytoplasmic reactivity. Only 2 cases showed a discordant E-cadherin/P120 immunoprofile (94% concordance). Significant staining differences among the 3 morphologic categories were not found. CDH1 mutation was found in 4 of 8 (50%) of cases, with 3 of 4 (75%) cases showing matched molecular/immunoprofile reactivity. No cases with CDH1 mutation showed discordant pattern E-cadherin/P120 immunoreactivity. Our rate of aberrant E-cadherin immunoreactivity in PUCs (73%) is similar to a meta-analysis of published cases (74%). We also report an identical rate of aberrant P120 immunoreactivity in PUCs (73%). While PUC remains a histologic diagnosis, in a subset of cases showing a less appreciated pattern (such as desmoplastic) or confounding cytoplasmic E-cadherin reactivity, the utility of paired P120 staining may be a useful diagnostic tool.

Cordial connections: molecular ensembles and structures of adhering junctions connecting interstitial cells of cardiac valves in situ and in cell culture.

Remarkable efforts have recently been made in the tissue engineering of heart valves to improve the results of valve transplantations and replacements, including the design of artificial valves. However, knowledge of the cell and molecular biology of valves and, specifically, of valvular interstitial cells (VICs) remains limited. Therefore, our aim has been to determine and localize the molecules forming the adhering junctions (AJs) that connect VICs in situ and in cell culture. Using biochemical and immunolocalization methods at the light- and electron-microscopic levels, we have identified, in man, cow, sheep and rat, the components of VIC-connecting AJs in situ and in cell culture. These AJs contain, in addition to the transmembrane glycoproteins N-cadherin and cadherin-11, the typical plaque proteins alpha- and beta-catenin as well as plakoglobin and p120, together with minor amounts of protein p0071, i.e. a total of five plaque proteins of the armadillo family. While we can exclude the occurrence of desmogleins, desmocollins and desmoplakin, we have noted with surprise that AJs of VICs in cell cultures, but not those growing in the valve tissue, contain substantial amounts of the desmosomal plaque protein, plakophilin-2. Clusters of AJs occur not only on the main VIC cell bodies but are also found widely dispersed on their long filopodia thus forming, in the tissue, a meshwork that, together with filopodial attachments to paracrystalline collagen fiber bundles, establishes a three-dimensional suprastructure, the role of which is discussed with respect to valve formation, regeneration and function.

δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer.

δ-Catenin, a member of the p120-catenin subfamily of armadillo proteins, reportedly increases during the late stage of prostate cancer. Our previous study demonstrates that δ-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind δ-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that δ-catenin enhances the protein stability of EGFR by inhibiting its lysosomal degradation that is mediated by c-casitas b-lineage lymphoma (c-Cbl), a RING domain E3 ligase. c-Cbl monoubiquitinates EGFR and thus facilitates its internalization, followed by lysosomal degradation. We observed that δ-catenin plays a key role in EGFR stability and downstream signaling. δ-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR. This in turn increases the expression of membrane bound EGFR and enhances EGFR/Erk1/2 signaling. Our findings add a new perspective on the role of δ-catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer.

[Expresion of E-cadherin and catenins in urothelial carcinomas]. / Expresión de cadherina E y cateninas en los carcinomas uroteliales.

OBJECTIVE: We examined the presence of E-cadherin and alpha, beta and gamma catenins detected by immunohistochemistry and correlated with the classic variables: grade, stage and recurrence. MATERIAL AND METHOD: The authors evaluated 37 transitional cell carcinomas. Biopsy specimens included no recurrent transitional cell carcinoma (n=19) and recurrent transitional cell carcinoma (n=18). Association of E-cadherin and alpha, beta and gamma catenins immunoreactivity with tumor grade, clinical stage and tumor recurrence was examined. RESULTS: E-cadherin and gamma catenin expression were related to the clinical stage of the disease, alpha and beta catenins were not correlated with grade, stage and recurrence of disease. CONCLUSIONS: Decreased E cadherin and gamma catenin expression were associated with advanced stage of the disease.

Lithium increases synaptic GluA2 in hippocampal neurons by elevating the δ-catenin protein.

Lithium (Li+) is a drug widely employed for treating bipolar disorder, however the mechanism of action is not known. Here we study the effects of Li+ in cultured hippocampal neurons on a synaptic complex consisting of δ-catenin, a protein associated with cadherins whose mutation is linked to autism, and GRIP, an AMPA receptor (AMPAR) scaffolding protein, and the AMPAR subunit, GluA2. We show that Li+ elevates the level of δ-catenin in cultured neurons. δ-catenin binds to the ABP and GRIP proteins, which are synaptic scaffolds for GluA2. We show that Li+ increases the levels of GRIP and GluA2, consistent with Li+-induced elevation of δ-catenin. Using GluA2 mutants, we show that the increase in surface level of GluA2 requires GluA2 interaction with GRIP. The amplitude but not the frequency of mEPSCs was also increased by Li+ in cultured hippocampal neurons, confirming a functional effect and consistent with AMPAR stabilization at synapses. Furthermore, animals fed with Li+ show elevated synaptic levels of δ-catenin, GRIP, and GluA2 in the hippocampus, also consistent with the findings in cultured neurons. This work supports a model in which Li+ stabilizes δ-catenin, thus elevating a complex consisting of δ-catenin, GRIP and AMPARs in synapses of hippocampal neurons. Thus, the work suggests a mechanism by which Li+ can alter brain synaptic function that may be relevant to its pharmacologic action in treatment of neurological disease.

Correlation between E-cadherin and p120 expression in invasive ductal breast cancer with a lobular component and MRI findings.

Invasive breast cancer comprises a spectrum of histological changes with purely lobular cancer on one side and purely ductal cancer on the other, with many mixed lesions in between. In a previous study, we showed that in patients with any percentage lobular component at core needle biopsy, preoperative MRI leads to the detection of clinically relevant additional findings in a substantial percentage of patients, irrespective of the percentage of the lobular component. Detection of a small lobular component may however not be reproducible among pathologists. Loss of membrane expression of E-cadherin or p120 is useful biomarkers of ILC and may therefore support a more objective diagnosis. All patients diagnosed with breast cancer containing a lobular component of any percentage between January 2008 and October 2012 were prospectively offered preoperative MRI. Clinically relevant additional findings on MRI were verified by pathology evaluation. Expression patterns of E-cadherin and p120 were evaluated by immunohistochemistry on the core needle biopsy. MRI was performed in 109 patients. The percentage of lobular component was significantly increased in cases with aberrant E-cadherin or p120 expression (both p = <0.001). However, aberrant expression of E-cadherin and p120 was not related to the probability of detecting relevant additional MRI findings. E-cadherin and p120 did not appear to be useful objective biomarkers for predicting additional relevant findings on MRI in patients with a lobular component in the core needle of their breast cancer.

Derangement of the E-cadherin/catenin complex is involved in transformation of differentiated to anaplastic thyroid carcinoma.

BACKGROUND: Anaplastic thyroid cancer arises, or transforms, from pre-existing differentiated thyroid cancer. E-cadherin functions as a cell-cell adhesion molecule that complexes with catenin proteins for function. The objective of this study was to evaluate the change in E-cadherin/beta-catenin expression in the transformation of differentiated to anaplastic thyroid carcinoma. METHODS: A tissue microarray was constructed from 12 anaplastic thyroid tumors and their adjacent associated differentiated foci. Immunohistochemistry was used to evaluate tumor expression of E-cadherin and beta-catenin. RESULTS: There was decreased expression of E-cadherin and beta-catenin by the anaplastic tumors when compared with the differentiated thyroid tumors from which they evolved. The expression of E-cadherin and beta-catenin was 92% and 67%, respectively, by the differentiated thyroid carcinoma, and 17% and 50%, respectively, by the anaplastic tumors. CONCLUSIONS: This report shows that derangement of the E-cadherin/catenin complex is associated with the transformation of differentiated into anaplastic thyroid carcinoma.

P120ctn may participate in epithelial-mesenchymal transition in OSCC.

AIM: Oral squamous cell carcinoma (OSCC) is the eighth most common cause of cancer death. OSCC cells can easily invade tissues and metastasize to the cervical lymph nodes. Understanding the molecular basis of OSCC metastasis would facilitate the development of new therapeutic approaches to the disease. MATERIALS AND METHODS: To identify the potential role of catenin (P120ctn) in the progression of OSCC, HN4 cells (derived from a primary OSCC) and HN12 cells (derived from a lymph node metastasis in the same patient) were used in the present study. The samples of 28 patients with OSCC were examined to determine the expression of P120ctn and E-cadherin (E-cad; E: Epithelial) in vivo. Then, P120ctn was subsequently knocked down in HN4 cells (HN4/shP120ctn) and overexpressed in HN12 cells (HN12/P120ctn). Invasion and migration capacity, as well as the expression of the epithelial-to-mesenchymal transition (EMT) markers N-cadherin and vimentin were detected. RESULTS: The results showed a positive correlation between the expression of P120ctn and E-cad in OSCC samples. The overexpression of P120ctn led to a decrease in both invasion and migration capacity of HN12 cells accompanied by a decrease in EMT markers. In contrast, knockdown of P120ctn led to an increase in both invasion and migration capacity accompanied by an increase in EMT markers. CONCLUSION: Considered together, we concluded that P120ctn might regulate EMT in OSCC through E-cad. The proper expression of P120ctn might therefore serve as a therapeutic goal for the inhibition of OSCC progression.

Cadherins and catenins in clival chordomas: correlation of expression with tumor aggressiveness.

The local invasiveness and occasional rapid growth of chordomas, despite optimal treatment, highlight the need to develop ways to predict their biologic behavior. Alterations in adhesion proteins have been shown to participate in proliferation, invasiveness, and metastasis in epithelial tumors. We therefore analyzed the expression of E-cadherin, N-cadherin, as well as their cytosolic binding proteins alpha-catenin, beta-catenin, and gamma-catenin, in 51 paraffin archived and 17 cryopreserved chordoma specimens. In the majority of chordomas, E-cadherin and N-cadherin expression was inversely correlated, whereas beta-catenin and gamma-catenin expression was directly correlated. By multivariate analysis, N-cadherin up-regulation correlated with a diminished recurrence-free survival, and E-cadherin down-regulation strongly correlated with increased probabilities of death as determined by the Kaplan-Meier log-rank test. There was a 3.28-fold increased probability of having a tumor recurrence and a 10.98-fold increased probability of dying when, respectively, N-cadherin was up-regulated and E-cadherin down-regulated. These results suggest that changes in the relative expression of the cadherin-catenin complex reflect chordoma aggressiveness; and that decreased expression of E-cadherin and increased expression of N-cadherin may underlie the transition from a less to a more aggressive tumor phenotype.

Characterization of α-, ß- and p120-Catenin Expression in Feline Mammary Tissues and their Relation with E- and P-Cadherin.

BACKGROUND: Abnormal catenin expression has been related to mammary carcinogenesis in both human and canine species and they are considered tumor- and invasion-suppressor molecules; however, in feline mammary tissues they have been scarcely studied. MATERIALS AND METHODS: The immunohistochemical expression of α-, ß- and p120-catenin was studied in a series of normal feline mammary glands, hyperplastic/dysplastic lesions and benign and malignant mammary tumors. Their relationship with clinicopathological parameters and with E- and P-cadherin expression was assessed. RESULTS: Normal tissues, hyperplastic/dysplastic lesions and benign tumors expressed α-, ß- and p120-catenin in the membrane of more than 75% of the luminal epithelial cells, while in malignant tumors, there was a reduction in their membranous expression and a p120-catenin cytoplasmic expression in 40%. Reduced α-catenin expression was related to tumor features with prognostic value, namely tumor size (p=0.0203) and necrosis (p=0.0205). The expression of α-, ß- and p120-catenin were individually related to each other and collectively associated with E-cadherin expression. CONCLUSION: The results demonstrate a relationship between feline mammary carcinogenesis and decreased expression of catenins, suggesting that they may represent a valuable tool in the diagnosis of feline mammary neoplasms.

Epithelial-mesenchymal transition (EMT) markers have prognostic impact in multiple primary oral squamous cell carcinoma.

Multiple primary tumors can occur in up to 35 % of the patients with head and neck cancer, however its clinicopathological features remain controversial. Deregulation of epithelial-mesenchymal transition (EMT) signaling has been associated with aggressive malignancies and tumor progression to metastasis in several cancer types. This study is the first to explore EMT process in multiple primary oral squamous cell carcinomas (OSCC). Immunohistochemical analysis of E-cadherin, catenin (α, ß, and γ), APC, collagen IV, Ki-67, cyclin D1, and CD44 were performed in a tissue microarray containing multiple representative areas from 102 OSCC patients followed-up by at least 10 years. Results were analysed in relation to clinicopathological characteristics and survival rates in patients presenting multiple primary tumors versus patients without second primary tumors or metastatic disease. Significant association was observed among multiple OSCCs and protein expression of E-cadherin (P = 0.002), ß-catenin (P = 0.047), APC (P = 0.017), and cyclin D1 (P = 0.001) as well as between lymph nodes metastasis and Ki-67 staining (P = 0.021). OSCCs presenting vascular embolization were associated with negative ß-catenin membrane expression (P = 0.050). There was a significantly lower survival probability for patients with multiple OSCC (log-rank test, P < 0.0001), for tumors showing negative protein expression for E-cadherin (log-rank test, P = 0.003) and ß-catenin (log-rank test, P = 0.031). Stratified multivariate survival analysis revealed a prognostic interdependence of E-cadherin and ß-catenin co-downexpression in predicting the worst overall survival (log-rank test, P = 0.007). EMT markers have a predicted value for invasiveness related to multiple primary tumors in OSCC and co-downregulation of E-cadherin and ß-catenin has a significant prognostic impact in these cases.