Osteopontin (OPN) and splice variants of CD44 (CD44 V ) have independently been identified as markers for tumor progression. In this study, we show that both OPN and CD44 V are frequently overexpressed in human gastric cancer and that OPN-engaged CD44 V ligation confers cells an increased survival mediated through integrin activation. First, we show that OPN treatment confers cells an increased resistance to UV-induced apoptosis. The OPN-mediated antiapoptosis is dependent on the expression of the variant exon 6 (V6)-or V7-containing CD44 as shown by overexpression of individual CD44 V in gastric AZ521 cells that express no or very low level of endogenous CD44 and by knockdown of the constitutively expressed V6-containing CD44 isoforms in colon HT29 cells. Although OPN also interacts with RGD integrins, OPN-RGD sequence is dispensable for OPN-mediated antiapoptosis. OPN-induced antiapoptosis is mainly attributed to the engagement of CD44 V isoforms and the relay of an insideout signaling via Src activity, leading to robust integrin activation. Furthermore, OPN-elicited antiapoptosis was observed when cells were plated on fibronectin but not on poly-D-lysin, and preincubation of cells with anti-integrin B 1 antibody to block integrin-extracellular matrix (ECM) interaction or ectopic expression of the dominant-negative forms of focal adhesion kinase to block ECM-derived signal abolished OPN-induced survival, suggesting that OPN-elicited antiapoptotic function is propagated from matrix transduced by integrin. Taken together, we showed that OPN-CD44 V interaction promotes ECM-derived survival signal mediated through integrin activation, which may play an important role in the pathogenic development and progression of gastric cancer. [Cancer Res 2007;67(5):2089-97]
Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53%), 20q13-qter (48%), 1p32-p36 (42%), 22q12-qter (27%), 17p13-pter (24%), 16p13-pter (21%), 6p21-pter (19%), 20p12-pter (19%), 7p21-pter (18%), 3q28-qter (8%), and 13q13-q14 (8%), and losses at 18q12-qter (11%), 3p12 (8%), 3p25-pter (8%), 5q14-q23 (8%), and 9p21-p23 (5%), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.
Ca؉2 /calmodulin-dependent protein kinases (CaMKs) are activated upon binding of Ca ؉2 /calmodulin. To gain maximal activity, CaMK I and CaMK IV can be further phosphorylated by an upstream kinase, CaMK kinase (CaMKK). We previously isolated cDNA clones encoding human CaMKK  isoforms that are heterogeneous in their 3-sequences (Hsu, L.-S., Tsou, A.-P., Chi, C.-W., Lee, C.-H., and Chen, J.-Y. (1998) J. Biomed. Sci. 5, 141-149). In the present study, we examined the genomic organization and transcription of the human CaMKK  gene. The human CaMKK  locus spans more than 40 kilobase pairs and maps to chromosome 12q24.2. It is organized into 18 exons and 17 introns that are flanked by typical splice donor and acceptor sequences. Two major species of transcripts, namely the 1 (5.6 kilobase pairs) and 2 (2.9 kilobase pairs), are generated through differential usage of polyadenylation sites located in the last and penultimate exons. Additional forms of CaMKK  transcripts were also identified that resulted from alternative splicing of the internal exons 14 and/or 16. These isoforms display differential expression patterns in human tissues and tumor-derived cell lines. They also exhibit a distinct ability to undergo autophosphorylation and to phosphorylate the downstream kinases CaMK I and CaMK IV. The differential expression of CaMKK  isoforms with distinct activity further suggests the complexity of the regulation of the CaMKK/CaMK cascade and an important role for CaMKK in the action of Ca ؉2 -mediated cellular responses.
Novel tricyclic 4‐(trifluoromethyl)‐[1,2,3]triazolo[1,5‐a]quinoxalines were readily prepared from N‐(o‐haloaryl)alkynylimines and sodium azide via copper(I)‐catalyzed tandem reactions. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.
Supplementary Figure 1 Legend from Osteopontin Promotes Integrin Activation through Outside-In and Inside-Out Mechanisms: OPN-CD44<sub>V</sub> Interaction Enhances Survival in Gastrointestinal Cancer Cells
Supplementary Figure 1 from Osteopontin Promotes Integrin Activation through Outside-In and Inside-Out Mechanisms: OPN-CD44<sub>V</sub> Interaction Enhances Survival in Gastrointestinal Cancer Cells
Supplementary Figure 1 Legend from Osteopontin Promotes Integrin Activation through Outside-In and Inside-Out Mechanisms: OPN-CD44<sub>V</sub> Interaction Enhances Survival in Gastrointestinal Cancer Cells
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