Expression of focal adhesion kinase gene and invasive cancer

Weiner, Timothy M.; Craven, Roll J.; Cance, William G.; Et, Liu

doi:10.1016/0140-6736(93)92881-s

Cited by 303 publications

(226 citation statements)

References 8 publications

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“…FAK expression was frequently increased in various cancer tissues, including colorectal cancer, and its upregulation was associated with poor prognosis and anoikis resistance (Lark et al, 2003;Owens et al, 1995;Weiner et al, 1993). Metastasis occurs through a series of sequential steps in which tumor cells first migrate from the primary tumor, penetrate blood vessels and colonize distant sites.…”

Section: Discussionmentioning

confidence: 99%

XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway

et al. 2009

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Colorectal cancers with mutations in the p53 gene have an invasive property, but its underlying mechanism is not fully understood. Through the screening of two data sets of the genome-wide expression profile, one for p53-introduced cells and the other for the numbers of cancer tissues, we report here X-linked ectodermal dysplasia receptor (XEDAR), a member of the TNFR superfamily, as a novel p53 target that has a crucial role in colorectal carcinogenesis. p53 upregulated XEDAR expression through two p53-binding sites within intron 1 of the XEDAR gene. We also found a significant correlation between decreased XEDAR expressions and p53 gene mutations in breast and lung cancer cell lines (P ¼ 0.0043 and P ¼ 0.0122, respectively). Furthermore, promoter hypermethylation of the XEDAR gene was detected in 20 of 20 colorectal cancer cell lines (100%) and in 6 of 12 colorectal cancer tissues (50%), respectively. Thus, the XEDAR expression was suppressed to o25% of surrounding normal tissues in 12 of 18 colorectal cancer tissues (66.7%) due to either its epigenetic alterations and/or p53 mutations. We also found that XEDAR interacted with and subsequently caused the accumulation of FAS protein, another member of p53-inducible TNFR. Moreover, XEDAR negatively regulated FAK, a central component of focal adhesion. As a result, inactivation of XEDAR resulted in the enhancement of cell adhesion and spreading, as well as resistance to p53-induced apoptosis. Taken together, our findings showed that XEDAR is a putative tumor suppressor that could prevent malignant transformation and tumor progression by regulating apoptosis and anoikis.

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Section: Discussionmentioning

confidence: 99%

XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway

et al. 2009

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“…Furthermore, the prognosis of patients who overexpressed FAK was significantly less favourable than that of FAK-overexpression (À) patients. A number of reports have indicated that FAK may be up-regulated in human tumour cells of diverse origin (Weiner et al, 1993;Akasaka et al, 1995;Owens et al, 1995;Tremblay et al, 1996;McCormack et al, 1997;Cance et al, 2000). In some of these reports, there has been a suspected relationship between FAK expression and metastatic ability (Owens et al, 1995;Tremblay et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Cells derived from pp125 FAK À/À mouse embryos exhibit reduced migration as a result of impaired adhesion turnover (Ilic et al, 1995(Ilic et al, , 1996. Overexpression of FAK has been reported in a number of invasive human cancer cells (Weiner et al, 1993;Akasaka et al, 1995;Owens et al, 1995;Tremblay et al, 1996;McCormack et al, 1997;Cance et al, 2000). In some of these reports, there is a suspected relationship between FAK expression and metastatic ability.…”

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confidence: 99%

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

et al. 2003

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Focal adhesion kinase (p125 FAK ; 'FAK') is a tyrosine kinase that is localised to cellular focal adhesions and is associated with a number of other proteins, such as integrin adhesion receptors. We performed an immunohistochemical analysis of FAK protein expression to determine the relationship between FAK overexpression and clinicopathological factors in oesophageal squamous cell carcinoma (ESCC). We examined tissue specimens that had been removed from 91 patients with thoracic oesophageal cancer who had undergone surgery between 1983 and 2001. Immunohistochemical staining was performed by the standard streptavidin -biotin method. Seven human ESCC cell lines -TE-1, TE-2, TE-8, TE-13, TE-15, TT, and TTn -and one immortalized human keratinocyte cell line -HaCaT -were used in Western blot analysis. Immunostaining of FAK was seen in the cytoplasm of cancer cells, particularly in cells located in the invasive fronts of cancer nests. FAK overexpression was detected in 54 of the 91 patients (59.3%). Significant correlations were observed between FAK overexpression and cell differentiation (P ¼ 0.0057), depth of tumour invasion (P ¼ 0.0023), presence of regional lymph node metastasis (P ¼ 0.0097), number of lymph node metastases (P ¼ 0.0026), and disease stage (P ¼ 0.012). The survival rates of patients with FAK-overexpressing cancer were significantly lower than those of patients without FAK-overexpression cancer (P ¼ 0.006). The 5-year survival rate of patients without FAK overexpression was 69%, whereas that of patients with FAK overexpression was 38%. On Western blot analysis, FAK was expressed at a high level in TE-1, TE-8, TE-15, and TT cells, at a moderate level in TE-2 and TTn cells, and at a low level in TE13 and HaCaT cells. FAK phosphorylation at tyrosine 397 was demonstrated in proportion to the intensity of FAK in all cell lines except TE15 and HaCaT. In conclusion, FAK overexpression of ESCC was related to cell differentiation, tumour invasiveness, and lymph node metastasis. Consequently, patients with ESCC who had FAK overexpression had a poor prognosis.

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“…Growth factor(s) stimulation of cells is accompanied by a rapid increase in tyrosine phosphorylation of focal adhesion proteins, most notably, FAK, paxillin and talin. The activation of focal adhesion complexes, in turn, initiates a cascade of interactions with other proteins containing SH2/SH3 domains (such as vSrc, vCrk and vinculin) and/or with the components of Ras signaling (such as Grb2 and Sos) (Bergman et al, 1995;Schlaepfer et al, 1994;Weiner et al, 1993). In most cell types, tyrosine phosphorylation of FAK coincides with the tyrosine phosphorylation and association with a 66 kD protein (presumably paxillin) and these proteins co-localize in focal adhesions (Rankin and Rozengurt, 1994;Turner et al, 1995).…”

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confidence: 99%

Serine phosphorylation of paxillin by heregulin-β1: role of p38 mitogen activated protein kinase

et al. 1999

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The mechanisms through which heregulin (HRG) regulates the progression of breast cancer cells to a more invasive phenotype are currently unknown. Recently we have shown that HRG treatment of breast cancer cells leads to the formation of lamellipodia/ ®lopodia, and increased cell migration and invasiveness through the phosphatidylinositol 3-kinase (PI-3 kinase).Since the process of cell migration must involve changes in adhesion, we explored the potential HRG regulation of paxillin, a major cytoskeletal phosphoprotein of focal adhesion. We report that HRG stimulation of noninvasive breast cancer cells resulted in stimulation of p38 mitogen-activated protein kinase (p38 MAPK ), extracellular signal-regulated kinases (ERK) and PI-3K, and a concurrent unexpected increase in the level of paxillin phosphorylation on serine residue which was sensitive to protein-phosphatase 2b but not to protein tyrosine phosphatase 1. In addition, HRG triggered a rapid redistribution of paxillin to the perinuclear regions from the tyrosine-phosphorylated focal adhesions, and increased cell scattering. There was no e ect of HRG on the state of phosphorylation and localization of focal adhesion kinase. The HRG-induced increase in serine phosphorylation of paxillin and cell scattering were selectively inhibited by a speci®c inhibitor of p38 MAPK or a dominant-negative p38 MAPK mutant, but not by inhibitors of p42/44 MAPK or PI-3 kinase pathways. For the ®rst time our results have shown that HRG, a potent migratory growth factor stimulates serine phosphorylation of paxillin. These ®ndings suggest a role of p38 MAPKdependent signal transduction pathway(s) in serine phosphorylation and disassembly of the paxillin from the focal complexes during HRG-induced cell shape alterations and motility.

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Expression of focal adhesion kinase gene and invasive cancer

Cited by 303 publications

References 8 publications

XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway

XEDAR as a putative colorectal tumor suppressor that mediates p53-regulated anoikis pathway

FAK overexpression is correlated with tumour invasiveness and lymph node metastasis in oesophageal squamous cell carcinoma

Serine phosphorylation of paxillin by heregulin-β1: role of p38 mitogen activated protein kinase

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