Wnt-C59 arrests stemness and suppresses growth of nasopharyngeal carcinoma in mice by inhibiting the Wnt pathway in the tumor microenvironment

Wnt/β-catenin signaling is responsible for the generation of cancer stem cells (CSCs) in many human tumors, including nasopharyngeal carcinoma (NPC). Recent studies demonstrate that Wnt or PORCN inhibitor, Wnt-C59, inhibits tumor growth in MMTV-WNT1 transgenic mice. The effect of Wnt-C59 in human tumors is not clear. In this study, the NPC cell lines investigated manifest heterogeneous responses to Wnt-C59 treatment. Wnt-C59 decreased tumor growth of SUNE1 cells in mice immediately following the administration of Wnt-C59. Mice injected with HNE1 cells did not develop visible tumors after the treatment of Wnt-C59, while control mice developed 100% tumors. Wnt-C59 inhibited stemness properties of NPC cells in a dosage-dependent manner by arresting sphere formation in both HNE1 and SUNE1 cells. Thus, Wnt-C59 has the potential to eradicate CSCs in human tumors. Active β-catenin and Axin2 proteins were strongly expressed in stromal cells surrounding growing tumors, confirming the importance of Wnt signaling activities in the microenvironment being driving forces for cell growth. These novel findings confirm the ability of Wnt-C59 to suppress Wnt-driven undifferentiated cell growth in NPC. Both anti-Wnt signaling and anti-CSC approaches are feasible strategies in cancer therapy.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

Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells

Background and Aims: Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers. Methods: Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity. Results: We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including β-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules β-catenin, Oct4, Nanog, and Sox2. Isolated GEP high cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEP low counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice. Conclusions: Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy. © 2011 Cheung et al.published_or_final_versio

Cost of school scoliosis screening: a cohort analysis of 306,144 students followed until skeletal maturity

Session 5: ScoliosisINTRODUCTION/AIM: The cost of school scoliosis screening in a new cohort of students each year may be changed because of change in epidemiology or screening performance. Current cost evaluations were based on a combined cohort of students with limited generalizability to prospective students. Therefore, we aimed to examine the cost of school scoliosis screening over ...postprin

Ripple modulated electronic structure of a 3D topological insulator

3D topological insulators, similar to the Dirac material graphene, host linearly dispersing states with unique properties and a strong potential for applications. A key, missing element in realizing some of the more exotic states in topological insulators is the ability to manipulate local electronic properties. Analogy with graphene suggests a possible avenue via a topographic route by the formation of superlattice structures such as a moir\'e patterns or ripples, which can induce controlled potential variations. However, while the charge and lattice degrees of freedom are intimately coupled in graphene, it is not clear a priori how a physical buckling or ripples might influence the electronic structure of topological insulators. Here we use Fourier transform scanning tunneling spectroscopy to determine the effects of a one-dimensional periodic buckling on the electronic properties of Bi2Te3. By tracking the spatial variations of the scattering vector of the interference patterns as well as features associated with bulk density of states, we show that the buckling creates a periodic potential modulation, which in turn modulates the surface and the bulk states. The strong correlation between the topographic ripples and electronic structure indicates that while doping alone is insufficient to create predetermined potential landscapes, creating ripples provides a path to controlling the potential seen by the Dirac electrons on a local scale. Such rippled features may be engineered by strain in thin films and may find use in future applications of topological insulators.Comment: Nature Communications (accepted

Two-dimensional Dirac fermions in a topological insulator: transport in the quantum limit

Pulsed magnetic fields of up to 55T are used to investigate the transport properties of the topological insulator Bi_2Se_3 in the extreme quantum limit. For samples with a bulk carrier density of n = 2.9\times10^16cm^-3, the lowest Landau level of the bulk 3D Fermi surface is reached by a field of 4T. For fields well beyond this limit, Shubnikov-de Haas oscillations arising from quantization of the 2D surface state are observed, with the \nu =1 Landau level attained by a field of 35T. These measurements reveal the presence of additional oscillations which occur at fields corresponding to simple rational fractions of the integer Landau indices.Comment: 5 pages, 4 figure

A metaphyseal fracture rat model for mechanistic studies of osteoporotic bone healing

Most osteoporotic fractures occur at metaphyseal regions of long bones. The present study proposed a clinically relevant animal model that satisfied: i) induction of osteoporosis, ii) unilateral complete osteotomy at metaphysis, iii) internal fixation. 6 months old female Sprague-Dawley rats (n = 64) were randomly divided into the ovariectomised-metaphyseal osteotomy (OVX, n = 32) and metaphyseal osteotomy (SHAM, n = 32) groups. The metaphyseal-osteotomy model was created with a plate-fixation of the osteotomy and assessed by X-ray, micro-computed tomography, histomorphometry and mechanical testing at weeks 1, 3 and 6. X-ray results showed complete healing of metaphyseal osteotomy at week 6. Histology showed 3 stages of metaphyseal healing. Stage 1 was characterised by fibrous tissue, consisting of disorganised orientation of collagen fibres, and infiltration of immune cells. At stage 2, a transitional zone consisting of maturing fibrous tissue and differentiating mesenchymal cells with early trabecular bone formation and disorganised woven bone were observed. During stage 3, cortical bone ends unified and woven bone underwent transformation to lamellar bone. OVX group healing was significantly delayed when compared to SHAM samples. The study demonstrated that healing of osteoporotic osteotomy at the metaphyseal region was delayed in terms of radiography, histomorphometry and mechanical strength. These quantitative evaluations, along with histological features, may provide key references for future studies. The animal model may provide additional clinical relevance as most osteoporotic fracture in humans occurs at metaphyseal regions

Fully gapped topological surface states in Bi2_2Se3_3 films induced by a d-wave high-temperature superconductor

Topological insulators are a new class of materials, that exhibit robust gapless surface states protected by time-reversal symmetry. The interplay between such symmetry-protected topological surface states and symmetry-broken states (e.g. superconductivity) provides a platform for exploring novel quantum phenomena and new functionalities, such as 1D chiral or helical gapless Majorana fermions, and Majorana zero modes which may find application in fault-tolerant quantum computation. Inducing superconductivity on topological surface states is a prerequisite for their experimental realization. Here by growing high quality topological insulator Bi$_2$Se$_3$ films on a d-wave superconductor Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$ using molecular beam epitaxy, we are able to induce high temperature superconductivity on the surface states of Bi$_2$Se$_3$ films with a large pairing gap up to 15 meV. Interestingly, distinct from the d-wave pairing of Bi$_2$Sr$_2$CaCu$_2$O$_{8+\delta}$, the proximity-induced gap on the surface states is nearly isotropic and consistent with predominant s-wave pairing as revealed by angle-resolved photoemission spectroscopy. Our work could provide a critical step toward the realization of the long sought-after Majorana zero modes.Comment: Nature Physics, DOI:10.1038/nphys274