The elevated levels of 1,4-galactosyltransferase I (GalT I; EC 2.4.1.38) are detected in highly metastatic lung cancer PGBE1 cells compared with its less metastatic partner PGLH7 cells. Decreasing the GalT I surface expression by small interfering RNA or interfering with the surface of GalT I function by mutation inhibited cell adhesion on laminin, the invasive potential in vitro, and tyrosine phosphorylation of focal adhesion kinase. The mechanism by which GalT I activity is up-regulated in highly metastatic cells remains unclear. To investigate the regulation of GalT I expression, we cloned the 5-region flanking the transcription start point of the GalT I gene (؊1653 to ؉52). Cotransfection of the GalT I promoter/luciferase reporter and the Ets family protein E1AF expression plasmid increased the luciferase reporter activity in a dose-dependent manner. By deletion and mutation analyses, we identified an Ets-binding site between nucleotides ؊205 and ؊200 in the GalT I promoter that was critical for responsiveness to E1AF. It was identified that E1AF could bind to and activate the GalT I promoter by electrophoretic mobility shift assay in PGLH7 cells and COS1 cells. A stronger affinity of E1AF for DNA has contributed to the elevated expression of GalT I in PGBE1 cells. Stable transfection of the E1AF expression plasmid resulted in increased GalT I expression in PGLH7 cells, and stable transfectants migrated faster than control cells. Meanwhile, the content of the 1,4-Gal branch on the cell surface was increased in stably transfected PGLH7 cells. GalT I expression can also be induced by epidermal growth factor and dominant active Ras, JNK1, and ERK1. These data suggest an essential role for E1AF in the activation of the human GalT I gene in highly metastatic lung cancer cells.The enzyme 1,4-galactosyltransferase I (GalT I 1 ; EC 2.4.1.38) is a constitutively expressed type II membrane-bound glycoprotein in vertebrates (1). It is unusual that it resides in two distinct subcellular compartments, the trans-Golgi network and the cell surface (2, 3). In the trans-Golgi complex, GalT I is one of the key enzymes involved in the sugar chain synthesis that catalyzes the transfer of galactose from UDP-Gal to terminal N-acetylglucosamine, forming the Gal134GlcNAc structure (4). Cell surface GalT I acts as a recognition molecule and participates in a number of cellular interactions, including neurite extension, cell growth, spermegg interaction, cell spreading, and migration (5-9).Neoplasms undergo various changes in the carbohydrate moieties of their glycoconjugates, which indicate that the glycosyltransferases themselves may change in malignancies. Consistent with this hypothesis, the importance of specific sialyltransferases, fucosyltransferases, N-acetylglucosaminyltransferase in tumorigenesis, and metastasis has been demonstrated (10 -12).Although the precise role of oligosaccharides in metastasis is presently unknown, accumulated evidence has shown that a number of highly metastatic murine and human cell lines are ...
PRR11 is a potential candidate oncogene that has been implicated in the pathogenesis of lung cancer, however the role of PRR11 in gastric cancer is currently unclear. In the present study, we investigated the role of PRR11 in gastric cancer by evaluating its expression status in samples from a cohort of 216 patients with gastric cancer. PRR11 was found to be overexpressed in 107 (49.5%) patients by immunohistochemistry of tissue microarrays generated using the patient samples. Furthermore, PRR11 overexpression was found to correlate significantly with clinicopathologic features such as tumor invasion, tumor differentiation, and disease stage. Survival analysis of the cohort revealed that PRR11 is an independent prognostic factor for gastric cancer patients. PRR11 was stably silenced in a gastric carcinoma cell line using an shRNA-based approach, and treated cells showed decreased cellular proliferation and colony formation in vitro and cell growth in vivo, companied by decreased expression of CTHRC1 and increased expression of LXN, proteins involved in tumor progression. Evaluation of human gastric cancer samples demonstrated that PRR11 expression was also associated with increased CTHRC1 and decreased LXN expression. These data indicate that PRR11 may be widely activated in human gastric cancer and are consistent with the hypothesis that PRR11 functions as an oncogene in the development and progression of gastric cancer.
The PITSLRE protein kinases are parts of the large family of p34cdc2-related kinases. During apoptosis induced by some stimuli, specific PITSLRE isoforms are cleaved by caspase to produce a protein that contains the C-terminal kinase domain of the PITSLRE proteins (p110C). The p110C induces apoptosis when it is ectopically expressed in Chinese hamster ovary cells. In our study, similar induction of this p110C was observed during anoikis in NIH3T3 cells. To investigate the molecular mechanism of apoptosis mediated by p110C, we used the yeast two-hybrid system to screen a human fetal liver cDNA library and identified p21-activated kinase 1 (PAK1) as an interacting partner of p110C. The association of p110C with PAK1 was further confirmed by in vitro binding assay, in vivo coimmunoprecipitation, and confocal microscope analysis. The interaction of p110C with PAK1 occurred within the residues 210 -332 of PAK1. Neither association between p58 PITSLRE or p110 PITSLRE and PAK1 nor association between p110C and PAK2 or PAK3 was observed. Anoikis was increased and PAK1 activity was inhibited when NIH3T3 cells were transfected with p110C. Furthermore, the binding of p110C with PAK1 and inhibition of PAK1 activity were also observed during anoikis. Taken together, these data suggested that PAK1 might participate in the apoptotic pathway mediated by p110C.Apoptosis is a form of altruistic cell suicide, which is involved in many physiological processes, including tissue homeostasis, embryonic development, and immune response (1, 2). It is becoming increasingly clear that cell cycle regulators such as the p34cdc2 gene family could influence apoptosis (3-7). The PITSLRE protein kinases, which are coded by the gene localized to human chromosome 1p36.3 and a syntenic region of mouse chromosome 4, are parts of the large family of p34cdc2-related kinases (8 -14). There are at least 20 PITSLRE protein kinase isoforms, which are differentially expressed in mammalian tissues and regulate diverse cellular functions, including the cell cycle control, tumorigenesis, the regulation of RNA splicing or transcription, and so on (8, 10 -11,13-26). Studies indicated that several of the PITSLRE protein kinase isoforms might serve as effectors in apoptotic signaling pathways (15-18).During apoptosis induced by Fas or tumor necrosis factor, the action of p110C, a novel processed PITSLRE isoform resulting from the proteolysis of specific larger PITSLTR isoforms, significantly increased (15,18). Previous studies of our group and others (15,26) showed that apoptosis was increased when p110C was ectopically expressed in Chinese hamster ovary cells or SMMC 7721 hepatocarcinoma cells. These data suggested that p110C might play an important role in mediating apoptosis. In this study, we also detected the expression of p110C in NIH3T3 cells during anoikis, which is a form of apoptosis induced by the disruption of cell-matrix interaction. In agreement with the previous studies, a similar induction of p110C was observed during anoikis in NIH3T3 cells. It ...
Dysregulation of homeobox B7 (HOXB7), a member of the homeobox genes family, was suggested to play a role in regulation of tumorigenesis and metastases of some cancers. However, the functions of HOXB7 in association with lung adenocarcinoma (LAC) have not been investigated. The correlation between the level of HOXB7 expression and cancer progression in patients is not known. In this study, through analysis of 75 LAC samples and their corresponding normal lung epithelium tissues immunohistochemistry (IHC), we demonstrate that HOXB7 was overexpressed in LAC specimens compared to their paired normal lung epithelium tissues. Increased expression of HOXB7 was associated with poor clinical outcomes, correlating significantly with a short survival time in patients who had LAC. Moreover, HOXB7 expression level was correlated with the tumor status (P = 0.028), nodal status (P = 0.012) and tumor stage (P = 0.029) in lung adenocarcinoma. Silencing HOXB7 inhibited cell growth and metastases in vitro and in vivo. In conclusion, our results suggest that HOXB7 promotes LAC progression by enhancing proliferation and metastasis. The increased expression of HOXB7 in LAC is a potential prognostic indicator for patients, and HOXB7 could be a novel target for treatment of LAC patients.
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