Given a previous report that Bcl-w is expressed in gastric cancer cells, particularly in those of an infiltrative morphology, we investigated whether Bcl-w expression influences the invasiveness of gastric cancer cells. To accomplish this, Bcl-w was overexpressed in adherent types of gastric adenocarcinoma cell lines, and this was found to result in an increase in their migratory and invasive potentials. These effects were not induced when Bcl-2 was overexpressed in the same cell types. Consistently, Bcl-w, but not Bcl-2, overexpression increased matrix metalloproteinase-2 (MMP-2) expression, and synthetic or natural inhibitors of MMP-2 abolished Bcl-w-induced cell invasion. Bcl-w overexpression also activated phosphoinositide 3-kinase (PI3K), Akt, and Sp1, and the blocking effects of each of these components using pharmacologic inhibitors, dominant-negative mutants, or small interfering RNA abolished the ability of Bcl-w to induce MMP-2 and cell invasion. The inhibition of PI3K/Akt signaling also prevented Sp1 activation. Overall, our data suggest that Bcl-w, which was previously shown to enhance gastric cancer cell survivability, also promotes their invasiveness by inducing MMP-2 expression via the sequential actions of PI3K, Akt, and Sp1. (Cancer Res 2006; 66(10): 4991-5)

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Peroxiredoxins (PRDX) are a family of thiol-dependent peroxidases. Among the six mammalian members of this family, PRDX6 is the only protein that additionally exhibits phospholipase A 2 (PLA 2 ) activity. The physiologic role of this interesting PRDX6 feature is largely unknown at present. In this study, we show that PRDX6 increases the metastatic potential of lung cancer cells. Functional analyses of the enzymatic activities of PRDX6, using specific pharmacologic inhibitors and mutagenesis studies, reveal that both peroxidase and PLA 2 activities are required for metastasis. Specifically, peroxidase activity facilitates the growth of cancer cells, and PLA 2 activity promotes invasiveness. Further investigation of the latter event discloses that PLA 2 activity promotes accumulation of arachidonic acid, which, in turn, induces the invasive pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and urokinase-type plasminogen activator. This study is the first to define the functions of the enzymatic activities of PRDX6 in metastasis and to show the involvement of arachidonic acid in PRDX6 action in intact cells. These novel findings provide a significant step toward elucidating the role of PRDX6 in cancer and the mechanism of its action.

BackgroundThere has been an increase in the use of fine needle aspiration cytology (FNAC) for the diagnosis of parathyroid lesions (PLs). Differentiation between a thyroid lesion and a PL is not easy because of their similar features. We reviewed parathyroid aspirates in our institution and aimed to uncover trends in diagnostic criteria.MethodsWe selected 25 parathyroid aspirates (from 6 men and 19 women) confirmed surgically or immunohistochemically from 2006 to 2011.ResultsMajor architectural findings of PLs include scattered naked nuclei, loose clusters, a papillary pattern with a fibrovascular core, tight clusters, and a follicular pattern. These architectures were commonly admixed with one another. Cytological features included anisokaryosis, stippled chromatin, a well-defined cell border, and oxyphilic cytoplasm. Eighteen of the 25 patients were diagnosed with PL using FNAC. Seven patients had been misdiagnosed with atypical cells (n=2), benign follicular cells (n=2), adenomatous goiter (n=2) and metastatic carcinoma (n=1) in FNAC. Using clinicoradiologic data, the sensitivity of the cytological diagnosis was 86.7%. The cytological sensitivity decreased to 50% without this information.ConclusionsFNAC of PL is easily confused with thyroid lesions. A combination of cytological parameters and clinical data will be required to improve the diagnostic sensitivity of PLs.

Previous reports suggest that, in addition to its therapeutic effects, ionizing radiation (IR) increases the invasiveness of surviving cancer cells. Here, we demonstrate that this activity of IR in lung cancer cells is mediated by a signaling pathway involving p38 kinase, phosphoinositide 3-kinase, Akt, and matrix metalloproteinase (MMP-2). The invasion-promoting doses of IR also increased and reduced the levels of vimentin and E-cadherin, respectively, both of which are markers for the epithelial-mesenchymal transition (EMT). Interestingly, all of these malignant actions of IR were mimicked by the overexpression of Bcl-X L , a pro-survival member of the Bcl-2 family, in lung cancer cells. Moreover, both RNA and protein levels of Bcl-X L were elevated upon irradiation of the cells, and the prevention of this event using small-interfering RNAs of Bcl-X L reduced the ability of IR to promote invasion signals and EMT-associated events. This suggests that Bcl-X L functions as a signaling mediator of the malignant effects of IR. It was also demonstrated that IR enhances signal transducer and activator of transcription 3 (STAT3) phosphorylation, and the reduction of STAT3 levels via RNA interference prevented IR-induced Bcl-X L accumulation, and thus all the tested Bcl-X L -dependent events. Overall, the data suggest that IR induces Bcl-X L accumulation via STAT3, which then promotes cancer cell invasion and EMT-associated markers. Our findings demonstrate a novel function of Bcl-X L in cancer, and also advance our understanding of the malignant actions of IR significantly. (Cancer Sci 2010; 101: 1417-1423 A lthough ionizing radiation (IR) is widely utilized for cancer therapy, (1)(2)(3) recent studies have shown that IR also exerts undesirable effects on cancer cells. For example, the irradiation of various types of cancer cells, including glioma, (4) hepatocellular carcinoma, (5) pancreatic cancer, (6) and meningioma cells, (7) with sublethal doses of IR resulted in an increase in their invasiveness in culture. Moreover, a large number of studies using animal models have demonstrated that local radiotherapy administered to primary tumors speeds their metastatic growth in vivo, (8)(9)(10) thereby suggesting that besides its therapeutic effects, IR promotes the malignant behaviors of surviving cancer cells. This latter effect of IR is also consistent with the finding that local failure after radiotherapy increases the probability that distant metastasis will develop in cancer patients. (11) Therefore, preventing such undesirable action of IR may be an essential component of efforts to improve the efficacy of radiotherapy.In order to develop a strategy toward this objective, the mechanism by which IR promotes cancer cell invasion should be delineated. Previous studies using glioma cells have suggested that IR stimulates signaling components, such as p38 kinase, phosphoinositide 3-kinase (PI3K), and Akt, leading to matrix metalloproteinase-2 (MMP-2) expression and thus enhanced cell invasion.(4) The ability of IR to ind...