MBP-1 Suppresses Growth and Metastasis of Gastric Cancer Cells through COX-2

Abstract

INTRODUCTIONGastric cancer is one of the most frequent neoplasms and leading causes of cancer-related mortality worldwide (Terry et al., 2002;Executive Yuan, 2006). At present, curative surgery of its primary tumor and control of lymph node metastasis are still the mainstay of treatment for gastric cancer without distant metastasis . However, gastric cancer with distant metastasis remains incurable now. More than 95% of malignancies of the stomach are adenocarcinomas (Smith et al., 2006). The risk factors of human gastric cancer include diet, Helicobacter pylori infection, and accumulation of specific genetic alterations (Gonzalez et al., 2002;Ushijima and Sasako, 2004;Zheng et al., 2004). To date, the regulatory mechanism of aggressiveness in gastric cancer has not yet been clearly characterized. Therefore, it is essential to gain further insights into the physiology of gastric cancer and its accumulated genetic alterations.The inducible cyclooxygenase, COX-2, catalyzes the ratelimiting step in conversion of arachidonate into prostaglandin E 2 (PGE 2 ). It was shown that COX-2 expression is upregulated in gastric cancer (Ristimäki et al., 1997;Uefuji et al., 1998;Yamamoto et al., 1999;Lim et al., 2000). COX-2 expression is also correlated with depth of invasion, lymphatic vessel invasion, lymph node metastasis, and poor prognosis of human gastric carcinoma (Murata et al., 1999;Ohno et al., 2001;Shi et al., 2003;Chen et al., 2006). Epithelial-mesenchymal transition (EMT) plays a key role in development and tumorigenesis (for a review, see Thiery and Sleeman, 2006). In gastric cancer cells with fibroblastoid morphological changes, EMT signaling was suggested to promote motility and invasiveness through decreasing cell-cell adhesion (Katoh, 2005). Recently, COX-2 expression was found to enhance EMT stimulated by TGF-␤ through a PGE 2 -dependent manner in breast cancer (Neil et al., 2008). In this scenario, the induction of COX-2 expression in gastric cancer could further induce EMT to promote metastasis.The c-Myc promoter binding protein 1 (MBP-1), a negative regulator of c-myc expression, is ubiquitously expressed in normal human tissues (Ray et al., 1994 groove of the major c-Myc promoter, the P2 promoter (Chaudhary and Miller, 1995). The 37-kDa MBP-1 is produced by alternative translation initiation from ␣-enolase gene but without enzyme activity of enolase (Feo et al., 2000;Subramanian and Miller, 2000). So far, several MBP-1-associating proteins were identified, including histone deacetylase HDAC1 (Ghosh et al., 1999), MIP2A/sedlin (Ghosh et al., 2001), MEK5␣ (Ghosh et al., 2005a), NS1-BP (Perconti et al., 2007), and Notch1 receptor intracellular domain (Hsu et al., 2008). The downstream target genes of MBP-1 remain unclear exclusive of c-myc. It was reported that MBP-1 could regulate target genes at least through p53-p21 pathway (Ghosh et al., 2008). Mounting evidence indicates that both MBP-1 and ␣-enolase are involved in tumorigenesis of breast carcinoma (Ray et al., 1995), nonsmall cell lung cancer (Chan...

Stem Cell Associated Genes Working with One MiRNA Cluster Have Different Clinic Pathologic Values in Gastric Cancer

“…C-Myc is a well known oncogenic molecule in many types of tumors. As the transcriptional suppressor of c-myc, MBP-1 was recently reported to be a suppressor of metastasis in stomach cancer [26], which indirectly demonstrated a predictive value of c-Myc in metastasis of gastric cancer.…”

Notch1 pathway-mediated microRNA-151-5p promotes gastric cancer progression

“…Whole-cell extracts were prepared and then Western blot analysis was performed with anti-Notch1 C-terminal, anti-E-cadherin, anti-plakoglobin, anti-vimentin, anti-p53 (Santa Cruz), anti-N-cadherin (BD Biosciences), anti-cleaved Notch1, anti-FAK (Cell Signaling Technology), anti-pFAK Y397 (Invitrogen), and anti-GAPDH (Biogenesis) antibodies [45]. …”

“…Both xenografted tumorigenicity and tail vein metastasis assays were performed as described [5, 45]. Briefly, the treated cells were subcutaneously injected into 5-week-old BALB/c nu/nu mice purchased from National Science Council Animal Center (Taipei, Taiwan) for xenografted tumorigenicity assay.…”

“…Volume of xenografts was examined and recorded every 3 days. For tail vein metastasis assay, the treated cells were injected into 6-week-old female NOD-SCID mice (National Taiwan University, Taipei, Taiwan) by tail vein injection [45]. Count of metastatic nodules in lung was measured by gross and microscopic examination after sacrificing.…”

Myc Promoter-Binding Protein-1 (MBP-1) Is a Novel Potential Prognostic Marker in Invasive Ductal Breast Carcinoma

“…So far, several MBP-1-associated proteins have been identified, including histone deacetylase HDAC1 [14], MIP2A/sedlin [15], [16], MEK5α [17], NS1-BP [18], and the Notch1 receptor intracellular domain [19]. The target genes of MBP-1 transcriptional activity remain unclear except for c-myc and, as recently reported, COX2 [20]. It has been reported that MBP-1 may regulate target genes at least in part through the p53–p21 pathway [21].…”