Adhesion-mediated squamous cell carcinoma survival through ligand-independent activation of epidermal growth factor receptor.

Department of Stomatology, School of Medicine, University of California at San Francisco, Box 0512, Room HSW-604, San Francisco, CA 94143-0512, USA.
American Journal Of Pathology (Impact Factor: 4.6). 11/2004; 165(4):1315-29. DOI: 10.1016/S0002-9440(10)63390-1
Source: PubMed

ABSTRACT The survival and growth of squamous epithelial cells require signals generated by integrin-matrix interactions. After conversion to squamous cell carcinoma, the cells remain sensitive to detachment-induced anoikis, yet in tumor cell aggregates, which are matrix-deficient, these cells are capable of suprabasal survival and proliferation. Their survival is enhanced through a process we call synoikis, whereby junctional adhesions between neighboring cells generate specific downstream survival signals. Here we show that in squamous cell carcinoma cells, E-cadherin-mediated cell-cell contacts specifically induce activation of epidermal growth factor receptor (EGFR). EGFR activation in turn triggers the ERK/MAPK signaling module, leading to elevation of anti-apoptotic Bcl-2. After intercellular adhesion, formation of adherens junctions triggers the formation of E-cadherin-EGFR complexes, correlating with EGFR transactivation. Analysis of the process with a dominant-negative EGFR mutant indicated that activation of EGFR is ligand-independent. Our data implicate cell-cell adhesion-induced activation of EGFR as a cooperative mechanism that generates compensatory survival signaling, protecting malignant cells from detachment-induced death.

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    ABSTRACT: The transcription factor PROX1 (prospero homeobox 1) has a critical role in the development of various organs, and has been implicated in both oncogenic and tumor-suppressive functions in human cancers. However, the role of PROX1 in the development of renal cell carcinomas (RCCs) has not yet been studied. Here, we reported that PROX1 expression was decreased in human RCC tissues compared with adjacent normal tissues. In RCC tissues, however, poorly differentiated RCC expressed higher PROX1 levels compared with well-differentiated RCC. In addition, the PROX1 immunostaining levels were positively correlated with tumor nuclear grade and lymph node metastasis. Further, high PROX1 expression indicated poor survival for patients. These findings imply that in the different developmental stages of RCC, PROX1 may exert distinct functions according to the specific microenvironment of tumor. Moreover, in vitro experiments revealed that PROX1 overexpression enhanced the proliferation and migration of RCC cells; conversely, PROX1 depletion by siRNA attenuated the proliferation and migration of RCC cells. Collectively, these observations suggest that PROX1 plays an important role in RCC development and progression, and PROX1 may be a novel target for prevention and treatment of RCC.
    PLoS ONE 05/2014; 9(5):e95996. · 3.53 Impact Factor
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    ABSTRACT: Epithelialisation is a m ajor component of wound healing and relies on migration and spreading of epidermal keratinocytes. An understanding of the mechanisms underlying this process h as salient clinical application, as wound healing m ay be pharmacologically modulated to enhance repair of tissue injury. Whilst the efficacy of commercially available hyaluronic acid (HA) formulations in skin tissue repair as well as its action on mesenchymal cells (e.g. fibroblasts and condrocytes) has been well documented, the role of HA in the process of keratinocyte epithelialisation still needs to be addressed i n detail. Here, we investigated the efficacy of Aminogam, a compound containing a pool of collagen precursor synthetic aminoacids (l-proline, l-leucine, l-lysine and glycine) combined with sodium hyaluronate (SH), in keratinocyte cytokinesis and epithelial wound repair in vitro. Our data show that after wounding, Aminogam-treated cells had higher rates of wound closure than untreated keratinocytes. Cell scattering of three-dimensional multicellular aggregates was 40% increased by Aminogam whereas cell spreading was not affected. Chemokinesis (random migration) and chemotaxis (directional migration) were enhanced by Aminogam at an early and later stage of migration, respectively. Silencing of β1 integrin in HaCat keratinocytes dramatically impaired epithelial cleft repair: wound healing, spreading, scattering and random/directional migration were all decreased 40 to 60% compared to controls. Aminogam could not improve (p > 0.05) any of these features in the absence of β1 integrin. Our data provide the first evidence that HA, namely Aminogam, exerts direct effects on keratinocyte motility via integrin β1.
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    ABSTRACT: IntroductionMatrix-detachment triggers anoikis, a form of apoptosis, in most normal epithelial cells, while acquisition of anoikis resistance is a prime requisite for solid tumor growth. Interestingly, recent studies have revealed that a small population of normal human mammary epithelial cells (HMECs) survive in suspension and generate multicellular spheroids termed as `mammospheres¿. Therefore, understanding how normal HMECs overcome anoikis may provide insights into breast cancer initiation and progression.Methods Primary breast tissue-derived normal HMECs were grown as adherent monolayers or mammospheres. The status of AMP-activated protein kinase (AMPK) and PEA15 signaling was investigated by immunoblotting. Pharmacological agents and RNA interference (RNAi) approach were employed to gauge their roles in mammosphere formation. Immunoprecipitation and in vitro kinase assays were undertaken to evaluate interactions between AMPK and PEA15. In vitro sphere formation and tumor xenograft assays were performed to understand their roles in tumorigenicity.ResultsIn this study we show that mammosphere formation by normal HMECs is accompanied with an increase in AMPK activity. Inhibition or knockdown of AMPK impaired mammosphere formation. Concomitant with AMPK activation, we detected increased Ser116 phosphorylation of PEA15, which promotes its anti-apoptotic functions. Inhibition or knockdown of AMPK impaired PEA15 Ser116 phosphorylation and increased apoptosis. Knockdown of PEA15, or overexpression of the non-phosphorylatable S116A mutant of PEA15, also abrogated mammosphere formation. We further demonstrate that AMPK directly interacts with and phosphorylates PEA15 at Ser116 residue, thus identifying PEA15 as a novel AMPK substrate. Together, these data revealed that AMPK activation facilitates mammosphere formation by inhibition of apoptosis, at least in part, through Ser116 phosphorylation of PEA15. Since anoikis resistance plays a critical role in solid tumor growth, we investigated the relevance of these findings in the context of breast cancer. Significantly, we show that the AMPK-PEA15 axis plays an important role in the anchorage-independent growth of breast cancer cells both in vitro and in vivo.Conclusions Our study identifies a novel AMPK-PEA15 signaling axis in the anchorage-independent growth of both normal and cancerous mammary epithelial cells, suggesting that breast cancer cells may employ mechanisms of anoikis resistance already inherent within a subset of normal HMECs. Thus, targeting the AMPK-PEA15 axis might prevent breast cancer dissemination and metastasis.
    Breast cancer research: BCR 08/2014; 16(4):420. · 5.88 Impact Factor


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