Physiological beta-catenin signaling controls self-renewal networks and generation of stem-like cells from nasopharyngeal carcinoma

BACKGROUND: A few reports suggested that low levels of Wnt signaling might drive cell reprogramming, but these studies could not establish a clear relationship between Wnt signaling and self-renewal networks. There are ongoing debates as to whether and how the Wnt/beta-catenin signaling is involved in the control of pluripotency gene networks. Additionally, whether physiological beta-catenin signaling generates stem-like cells through interactions with other pathways is as yet unclear. The nasopharyngeal carcinoma HONE1 cells have low expression of beta-catenin and wild-type expression of p53, which provided a possibility to study regulatory mechanism of stemness networks induced by physiological levels of Wnt signaling in these cells. RESULTS: Introduction of increased beta-catenin signaling, haploid expression of beta-catenin under control by its natural regulators in transferred chromosome 3, resulted in activation of Wnt/beta-catenin networks and dedifferentiation in HONE1 hybrid cell lines, but not in esophageal carcinoma SLMT1 hybrid cells that had high levels of endogenous beta-catenin expression. HONE1 hybrid cells displayed stem cell-like properties, including enhancement of CD24(+) and CD44(+) populations and generation of spheres that were not observed in parental HONE1 cells. Signaling cascades were detected in HONE1 hybrid cells, including activation of p53- and RB1-mediated tumor suppressor pathways, up-regulation of Nanog-, Oct4-, Sox2-, and Klf4-mediated pluripotency networks, and altered E-cadherin expression in both in vitro and in vivo assays. qPCR array analyses further revealed interactions of physiological Wnt/beta-catenin signaling with other pathways such as epithelial-mesenchymal transition, TGF-beta, Activin, BMPR, FGFR2, and LIFR- and IL6ST-mediated cell self-renewal networks. Using beta-catenin shRNA inhibitory assays, a dominant role for beta-catenin in these cellular network activities was observed. The expression of cell surface markers such as CD9, CD24, CD44, CD90, and CD133 in generated spheres was progressively up-regulated compared to HONE1 hybrid cells. Thirty-four up-regulated components of the Wnt pathway were identified in these spheres. CONCLUSIONS: Wnt/beta-catenin signaling regulates self-renewal networks and plays a central role in the control of pluripotency genes, tumor suppressive pathways and expression of cancer stem cell markers. This current study provides a novel platform to investigate the interaction of physiological Wnt/beta-catenin signaling with stemness transition networks.published_or_final_versio

PTPRG suppresses tumor growth and invasion via inhibition of Akt signaling in nasopharyngeal carcinoma

Protein Tyrosine Phosphatase, Receptor Type G (PTPRG) was identified as a candidate tumor suppressor gene in nasopharyngeal carcinoma (NPC). PTPRG induces significant in vivo tumor suppression in NPC. We identified EGFR as a PTPRG potential interacting partner and examined this interaction. Dephosphorylation of EGFR at EGFR-Y1068 and -Y1086 sites inactivated the PI3K/Akt signaling cascade and subsequent down-regulation of downstream pro-angiogenic and -invasive proteins (VEGF, IL6, and IL8) and suppressed tumor cell proliferation, angiogenesis, and invasion. The effect of Akt inhibition in NPC cells was further validated by Akt knockdown experiments in the PTPRG-down-regulated NPC cell lines. Our results suggested that inhibition of Akt in NPC cells induces tumor suppression at both the in vitro and in vivo levels, and also importantly, in vivo metastasis. In conclusion, we confirmed the vital role of PTPRG in inhibiting Akt signaling with the resultant suppression of in vivo tumorigenesis and metastasis.published_or_final_versio

Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma

© 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 × 10 -9 ), but was less obvious in other types of solid tumors except for prostate and Epstein-Barr virus (EBV)-positive gastric cancer (FDR < 10 -3 ). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection.published_or_final_versio

Metastasis-suppressing <i>NID2</i>, an epigenetically-silenced gene, in the pathogenesis of nasopharyngeal carcinoma and esophageal squamous cell carcinoma

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Functional investigation of tumor and angiogenesis suppressive candidate tumor suppressor, cysteine-rich intestinal protein 2 in nasopharyngeal carcinoma

Session 8 - Epithelial cells, Infection, Carcinoma: abstract no. 55postprintThe 14th Biennial Symposium of the International Association for Research on Epstein-Barr Virus and Associated Diseases (EBV 2010), Birmingham, U.K., 4-7 September 2010

THSD1: a candidate tumor suppressor attenuates angiogenesis, migratory and invasive potential of endothelial cells

Croucher ASI - The Croucher Foundation Advanced Study Institut

Tumor suppressive and angiogenic role of THSD1 in esophageal squamous cell carcinoma and nasopharyngeal carcinoma

Poster Session 5 - Novel Tumor Suppressor Genes 1: abstract no. 3061BACKGROUND AND AIMS: Loss of chromosome 13q regions is a frequent event in both esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). By microcell-mediated chromosome transfer, chromosome 13 was demonstrated to play a significant tumor suppressive role in both ESCC and NPC in our laboratory. THSD1 is a novel candidate tumor suppressor gene (TSG) previously identified by microarray differential gene expression profiling. It encodes a transmembrane molecule containing a thrombospondin type 1 repeat (TSR), which may be involved in cell adhesion and angiogenesis. Proteins possessing the TSR, such as thrombospondin-1 (Tsp1), ADAM metallopeptidase with thrombospondin type 1 motif, 1 (ADAMTS1) and ADAMTS8, regulate angiogenesis. We previously showed that the ...link_to_OA_fulltextThe 101st Annual Meeting of the American Association for Cancer Research (AACR 2010), Washington, DC., 17-21 April 2010

Can a scavenging gastropod with a mussel conspecific diet induce anti-predator defence in the mussel Perna viridis?

This study investigated whether a mussel predator (the swimming crab Thalamita danae) and a scavenger (the gastropod Babylonia lutosa) could induce anti-predator response in the green-lipped mussel Perna viridis by chemical means. The crabs and gastropods had been either starved or recently fed with the mussels. We examined the number, diameter, length and volume of byssus threads produced by the mussels in order to compare the intensity of anti-predator responses when they were exposed to different stimuli. Our results showed that the mussels produced a significantly larger volume of byssus threads when they were exposed to a crab that had recently consumed conspecifics than the mussels in the control group. The starved crab had a weak effect on increasing the number, length, diameter and volume of byssus threads. Furthermore, the scavenging gastropods failed to increase byssus thread production in the mussels, no matter they had been starved or consumed conspecifics. Indeed, byssus thread production is energetically costly. It would be maladaptive for the mussels to increase byssus thread production in response to a low predation risk presented by a scavenger. © 2011 Elsevier B.V.link_to_subscribed_fulltex

Characterization of PHF11, a candidate tumor suppressor gene, in esophageal squamous cell carcinoma

Poster Session 7 - Nuclear Oncogenes and Tumor Suppressor Genes: abstract no. 2181BACKGROUND AND AIMS: Esophageal squamous cell carcinoma (ESCC) has a high incidence in China, with five-year survival rates in Hong Kong of only 10.7%. Loss of chromosome 13q regions is a frequent event in ESCC. A candidate tumor suppressor gene (TSG), PHF11, located at 13q14.2 was identified from our previous chromosome transfer study and shows 100% down-regulation in 18 cancer cell lines, including 16 ESCC cell lines, compar...link_to_OA_fulltex

Physiological β-catenin signaling regulates pluripotency genes in cancer microcell hybrids

Poster Session 15 - Markers of Cancer Stem and iPS Cells: abstract no. 420Both β-catenin signaling and Nanog were previously reported to be involved in cell fusion-mediated somatic cell reprogramming. It remains unclear as to how the β-catenin signaling pathway is initiated and whether this pathway may directly control the expression of core stem cell factors such as Nanog and Oct4. Since β-catenin signaling is a predominating force for the regulation of cellular fate and basic levels of this signaling are needed for somatic cell reprogramming, we speculate that transfer of a single copy of chromosome 3, where β-catenin maps and is controlled by its natural regulators, into somatic cancer cells may appropriately induce this pathway and switch on the expression of endogenous pluripotency genes in recipient cells. We previously generated …link_to_OA_fulltextThe 103rd Annual Meeting of the American Association for Cancer Research (AACR 2012), Chicago, IL., 31 March-4 April 2012