Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays

Leethanakul, Chidchanok; Patel, Vyomesh; Gillespie, John W.; Pallente, Michael; Ensley, John F.; Koontongkaew, Sittichai; Liotta, Lance A.; Emmert‐Buck, Michael R.; Gutkind, J. Silvio

doi:10.1038/sj.onc.1203703

Cited by 264 publications

(180 citation statements)

References 14 publications

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“…Additionally, the connection between deregulated b-catenin signaling and cancer is also well documented. In fact, along with the commonly described mutations in either APC and/ or b-catenin associated with cancers of the colon, prostate, ovaries, brain, liver, and others (Morin, 1999), deregulated Wnt-1 expression has been described in head and neck basal cell carcinomas (Leethanakul et al, 2000). The regulatory link between Gadd45a and b-catenin is reflected in the fact that we detect dramatic increases in both expression and activity of key MMPs in epidermal keratinocytes.…”

Section: Discussionmentioning

confidence: 70%

Gadd45a regulates matrix metalloproteinases by suppressing ΔNp63α and β-catenin via p38 MAP kinase and APC complex activation

et al. 2003

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The p53-regulated growth arrest and DNA damageinducible gene product Gadd45a has been recently identified as a key factor protecting the epidermis against ultraviolet radiation (UVR)-induced skin tumors by activating p53 via the stress mitogen-activated protein kinase (MAPK) signaling pathway. Herein we identify Gadd45a as an important negative regulator of two oncogenes commonly over-expressed in epithelial tumors: the p53 homologue DNp63a and b-catenin. DNp63a is one of the several p63 isoforms and is the predominant species expressed in basal epidermal keratinocytes. DNp63a lacks the N-terminal transactivation domain and behaves as a dominant-negative factor blocking expression of several p53-effector genes. DNp63a also associates with and blocks activation of the adenomatous polyposis coli (APC) destruction complex that targets free cytoplasmic bcatenin for degradation. While most b-catenin protein is localized to the cell membrane and is involved in cell-cell adhesion, accumulation of free cytoplasmic b-catenin will translocate into the nucleus where it functions in a bipartite transcription factor complex, whose targets include invasion and metastasis promoting endopeptidases, matrix metalloproteinases (MMP). We show that Gadd45a not only directly associates with two components of the APC complex, namely protein phosphatase 2A (PP2A) and glycogen synthase kinase 3b (GSK3b) but also promotes GSK3b dephosphorylation at Ser9, which is essential for GSK3b activation, and resultant activation of the APC destruction complex. We demonstrate that lack of Gadd45a not only prevents DNp63a suppression and GSK3b dephosphorylation but also prevents free cytoplasmic b-catenin degradation after UV irradiation. The inability of Gadd45a-null keratinocytes to suppress b-catenin may contribute to the resulting observation of increased MMP expression and activity along with significantly faster keratinocyte migration in Matrigel in vitro and accelerated wound closure in vivo. Furthermore, epidermal keratinocytes treated with p38 MAPK inhibitors, both in vivo and in vitro, behave very similarly to Gadd45a-null keratinocytes after UVR. Similarly, Trp53-null mice are unable to attenuate DNp63a expression in epidermal keratinocytes after such stress. These findings demonstrate a dependence on Gadd45a-mediated p38 MAPK and p53 activation for proper modulation of DNp63a, GSK3b, and b-catenin after irradiation. Taken together, our results indicate that Gadd45a is able to repress DNp63a, b-catenin, and consequently MMP expression by two means: by maintaining UVR-induced p38 MAPK and p53 activation and also by associating with the APC complex. This implicates Gadd45a in the negative regulation of cell migration, and invasion.

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Section: Discussionmentioning

confidence: 70%

Gadd45a regulates matrix metalloproteinases by suppressing ΔNp63α and β-catenin via p38 MAP kinase and APC complex activation

et al. 2003

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“…On the other hand, notch signaling promotes differentiation in skin (Lefort and Dotto, 2004) and loss of function of notch is permissive for tumor formation in mouse models (Nicolas et al, 2003). Although two expression array studies found upregulation of some members of the wnt and notch signaling pathways in head and neck SCC (Leethanakul et al, 2000;Ha et al, 2003), the hedgehog and notch pathways have not been previously characterized in oral squamous cell tumorigenesis. Therefore, we investigated whether expression levels of other members of the hedgehog and notch pathways were altered in oral SCC.…”

Section: Resultsmentioning

confidence: 99%

Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma

et al. 2005

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“…52,53 Keratinocyte cell division is confined to the basal layer in which mitogenic guideposts are mediated by survival pathways through PI 3 K kinase and PKB/ AKT pathway. The observation is also correlated with increased DNp63 and cyclin D expression, c-myc phosphorylation and nuclear accumulation of b-catenin.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

Chang

Lin

Yang

et al. 2007

Intl Journal of Cancer

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Immortalization is a critical event in virus-related oncogenesis. No enough information, however, is currently available to elucidate the changes that occur in cellular molecules during immortalization. To identify potential cellular markers or regulators involving in immortalization, a paired-cell model of primary foreskin keratinocytes (FK) and HPV16 immortalized foreskin keratinocytes were established. Using mRNA differential display, RT-PCR and Northern blot methods, we have identified and confirmed that Dyrk1a (dual-specificity tyrosine-phosphorylated and regulated kinase 1A) is present and increased in HPV16 immortalized cells, but is absent in primary keratinocytes. Moreover, transfection of E7 siRNA oligo into immortalized cells leads to a diminishing E7 expression and the eventual disappearance of Dyrk1a. Similar results of Dyrk1a expressional differences could also be seen when tissue specimens were compared using LCM/real-time PCR and immunohistochemistry analysis; malignant cervical lesions contain significantly more DYRK1A than normal tissue. It was also demonstrated that raised DYRK1A could rearrange the cellular localization of FKHR (forkhead in rhabdomyosarcoma), an apoptosis activator, and suppress BAD. Importantly, this phenomenon can be reversed when endogenous Dyrk1a was knocked down in immortalized cells by RNA interference. These results suggest that the raised Dyrk1a in HPV16 immortalized keratinocytes and cervical lesions may serve as a candidate antiapoptotic factor in the FKHR regulated pathway and initiate immortalization and tumorigenesis gradually. ' 2007 Wiley-Liss, Inc.Key words: HPV16; keratinocytes; Dyrk1a; immortalization; apoptosis Mammalian cells have a limited life span and proliferating capacity when cultivated in vitro. Replicate senescence or the terminal arrest state, has been found to be accompanied by several molecular changes that lead to an activated suppression of the cell cycle and the shortening of the telomeres. 1 Similar to apoptosis, cellular senescence is thought to be a mechanism of tumor suppression because it prevents the outgrowth of cells that have acquired mutations in genes rendering them cancerous. Consistent with this model, several tumor suppressor genes (such as, overexpressed p16 or ZNF217, activated p53 and deregulated Rassf1a or c-myc, etc) or their products have been reported and shown to be associated in parallel with telomere irregularities at the onset of cellular senescence. 2 Telomere shortening has been shown to generate unstable DNA leading to p53 activation and the subsequent transcriptional induction of the cdk inhibitor p21 CIP13 that moves cells into senescence state. Therefore, preventing telomere erosion by ectopic expression of telomerase is sufficient to immortalized primary cells in vitro and thus extend life span. [4][5][6] Although it works in human fibroblast, telemorase alone, however, is not sufficient to induce immortalization in human keratinocytes and mammary epithelial cells. 7 To identify other factors that are involved ...

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Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays

Cited by 264 publications

References 14 publications

Gadd45a regulates matrix metalloproteinases by suppressing ΔNp63α and β-catenin via p38 MAP kinase and APC complex activation

Gadd45a regulates matrix metalloproteinases by suppressing ΔNp63α and β-catenin via p38 MAP kinase and APC complex activation

Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma

Increased expression of Dyrk1a in HPV16 immortalized Keratinocytes enable evasion of apoptosis

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