Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer.

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

Self-consistent implementation of locally scaled self-interaction-correction method.

Recently proposed local self-interaction correction (LSIC) method [Zope et al., J. Chem. Phys. 151, 214108 (2019)] is a one-electron self-interaction-correction (SIC) method that uses an iso-orbital indicator to apply the SIC at each point in space by scaling the exchange-correlation and Coulomb energy densities. The LSIC method is exact for the one-electron densities, also recovers the uniform electron gas limit of the uncorrected density functional approximation, and reduces to the well-known Perdew-Zunger SIC (PZSIC) method as a special case. This article presents the self-consistent implementation of the LSIC method using the ratio of Weizsäcker and Kohn-Sham kinetic energy densities as an iso-orbital indicator. The atomic forces as well as the forces on the Fermi-Löwdin orbitals are also implemented for the LSIC energy functional. Results show that LSIC with the simplest local spin density functional predicts atomization energies of the AE6 dataset better than some of the most widely used generalized-gradient-approximation (GGA) functional [e.g., Perdew-Burke-Ernzerhof (PBE)] and barrier heights of the BH6 database better than some of the most widely used hybrid functionals (e.g., PBE0 and B3LYP). The LSIC method [a mean absolute error (MAE) of 0.008 Å] predicts bond lengths of a small set of molecules better than the PZSIC-LSDA (MAE 0.042 Å) and LSDA (0.011 Å). This work shows that accurate results can be obtained from the simplest density functional by removing the self-interaction-errors using an appropriately designed SIC method.

Vertical detachment energies of ammonia cluster anions using self-interaction-corrected methods.

Systems with weakly bound extra electrons impose great challenges to semilocal density functional approximations (DFAs), which suffer from self-interaction errors. Small ammonia clusters are one such example of weakly bound anions where the extra electron is weakly bound. We applied two self-interaction correction (SIC) schemes, viz., the well-known Perdew-Zunger and the recently developed locally scaled SIC (LSIC) with the local spin density approximation (LSDA), Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation (GGA), and the SCAN meta-GGA functionals to calculate the vertical detachment energies (VDEs) of small ammonia cluster anions (NH3)n-. Our results show that the LSIC significantly reduces the errors in calculations of VDE with LSDA and PBE-GGA functionals leading to better agreement with the reference values calculated with coupled cluster singles and doubles with perturbative triples [CCSD(T)]. Accurate prediction of VDE as an absolute of the highest occupied molecular orbital (HOMO) is challenging for DFAs. Our results show that VDEs estimated from the negative of HOMO eigenvalues with the LSIC-LSDA and Perdew-Zunger SIC-PBE are within 11 meV of the reference CCSD(T) results. The LSIC method performs consistently well for the VDE estimates, from both the total energy differences and the absolute HOMO eigenvalues.

Study of Self-Interaction Errors in Density Functional Calculations of Magnetic Exchange Coupling Constants Using Three Self-Interaction Correction Methods.

We examine the role of self-interaction error (SIE) removal on the evaluation of magnetic exchange coupling constants. In particular, we analyze the effect of scaling down the self-interaction correction (SIC) for three nonempirical density functional approximations (DFAs) namely, the local spin density approximation, the Perdew-Burke-Ernzerhof generalized gradient approximation, and the recent SCAN family of meta-GGA functionals. To this end, we employ three one-electron SIC methods: Perdew-Zunger SIC [Perdew, J. P.; Zunger, A. Phys. Rev. B, 1981, 23, 5048.], the orbitalwise scaled SIC method [Vydrov, O. A. et al. J. Chem. Phys. 2006, 124, 094108.], and the recent local scaling method [Zope, R. R. et al. J. Chem. Phys. 2019, 151, 214108.]. We compute the magnetic exchange coupling constants using the spin projection and nonprojection approaches for sets of molecules composed of dinuclear and polynuclear H···He models, organic radical molecules, and chlorocuprate and compare these results against accurate theories and experiment. Our results show that for the systems that mainly consist of single-electron regions, PZSIC performs well, but for more complex organic systems and the chlorocuprates, an overcorrecting tendency of PZSIC combined with the DFAs utilized in this work is more pronounced, and in such cases, LSIC with kinetic energy density ratio performs better than PZSIC. Analysis of the results in terms of SIC corrections to the density and to the total energy shows that both density and energy correction are required to obtain an improved prediction of magnetic exchange couplings.

Proximity Band Structure and Spin Textures on Both Sides of Topological-Insulator/Ferromagnetic-Metal Interface and Their Charge Transport Probes.

The control of recently observed spintronic effects in topological-insulator/ferromagnetic-metal (TI/FM) heterostructures is thwarted by the lack of understanding of band structure and spin textures around their interfaces. Here we combine density functional theory with Green's function techniques to obtain the spectral function at any plane passing through atoms of Bi2Se3 and Co or Cu layers comprising the interface. Instead of naively assumed Dirac cone gapped by the proximity exchange field spectral function, we find that the Rashba ferromagnetic model describes the spectral function on the surface of Bi2Se3 in contact with Co near the Fermi level EF0, where circular and snowflake-like constant energy contours coexist around which spin locks to momentum. The remnant of the Dirac cone is hybridized with evanescent wave functions from metallic layers and pushed, due to charge transfer from Co or Cu layers, a few tenths of an electron-volt below EF0 for both Bi2Se3/Co and Bi2Se3/Cu interfaces while hosting distorted helical spin texture wounding around a single circle. These features explain recent observation of sensitivity of spin-to-charge conversion signal at TI/Cu interface to tuning of EF0. Crucially for spin-orbit torque in TI/FM heterostructures, few monolayers of Co adjacent to Bi2Se3 host spectral functions very different from the bulk metal, as well as in-plane spin textures (despite Co magnetization being out-of-plane) due to proximity spin-orbit coupling in Co induced by Bi2Se3. We predict that out-of-plane tunneling anisotropic magnetoresistance in Cu/Bi2Se3/Co vertical heterostructure can serve as a sensitive probe of the type of spin texture residing at EF0.

Loss of corepressor PER2 under hypoxia up-regulates OCT1-mediated EMT gene expression and enhances tumor malignancy.

The circadian clock gene Period2 (PER2) has been suggested to be a tumor suppressor. However, detailed mechanistic evidence has not been provided to support this hypothesis. We found that loss of PER2 enhanced invasion and activated expression of epithelial-mesenchymal transition (EMT) genes including TWIST1, SLUG, and SNAIL. This finding was corroborated by clinical observation that PER2 down-regulation was associated with poor prognosis in breast cancer patients. We further demonstrated that PER2 served as a transcriptional corepressor, which recruited polycomb proteins EZH2 and SUZ12 as well as HDAC2 to octamer transcription factor 1 (OCT1) (POU2F1) binding sites of the TWIST1 and SLUG promoters to repress expression of these EMT genes. Hypoxia, a condition commonly observed in tumors, caused PER2 degradation and disrupted the PER2 repressor complex, leading to activation of EMT gene expression. This result was further supported by clinical data showing a significant negative correlation between hypoxia and PER2. Thus, our findings clearly demonstrate the tumor suppression function of PER2 and elucidate a pathway by which hypoxia promotes EMT via degradation of PER2.

Giant thermoelectric effect in graphene-based topological insulators with heavy adatoms and nanopores.

Designing thermoelectric materials with high figure of merit ZT = S(2)GT/Ktot requires fulfilling three often irreconcilable conditions, that is, the high electrical conductance G, small thermal conductance Ktot, and high Seebeck coefficient S. Nanostructuring is one of the promising ways to achieve this goal as it can substantially suppress lattice contribution to Ktot. However, it may also unfavorably influence the electronic transport in an uncontrollable way. Here, we theoretically demonstrate that this issue can be ideally solved by fabricating graphene nanoribbons with heavy adatoms and nanopores. The adatoms locally enhance spin-orbit coupling in graphene thereby converting it into a two-dimensional topological insulator with a band gap in the bulk and robust helical edge states, which carry electrical current and generate a highly optimized power factor S(2)G per helical conducting channel due to narrow boxcar-function-shaped electronic transmission (surpassing even the Mahan-Sofo limit obtained for delta-function-shaped electronic transmission). Concurrently, the array of nanopores impedes the lattice thermal conduction through the bulk. Using quantum transport simulations coupled with first-principles electronic and phononic band structure calculations, the thermoelectric figure of merit is found to reach its maximum ZT ≃ 3 at low temperatures T ≃ 40 K. This paves a way to design high-ZT materials by exploiting the nontrivial topology of electronic states through nanostructuring.

Insulin-like growth factor 1 mediates 5-fluorouracil chemoresistance in esophageal carcinoma cells through increasing survivin stability.

Insulin-like growth factor 1 (IGF-1) inhibits 5-fluorouracil (5-Fu)-induced apoptosis in esophageal carcinoma cells; however, the mechanisms for IGF-1-induced 5-Fu chemoresistance remain unknown. In the human esophageal carcinoma cell line, CE48T/VGH, we show that IGF-1 up-regulated survivin expression at the post-transcriptional level and this up-regulation is mediated by both the PI3-K/Akt and casein kinase 2 signaling pathways. We then examine whether IGF-1-induced 5-Fu chemoresistance is mediated through up-regulation of survivin. Ectopic expression of survivin inhibits 5-Fu-induced apoptosis; furthermore, the abolition of survivin expression sensitizes cells to 5-Fu treatment and prevents the anti-apoptotic function of IGF-1 in esophageal carcinoma cell lines. We also found that ectopic expression of survivin or treatment with IGF-1 inhibits the release of Smac/DIABLO and caspases activation after 5-Fu treatment. Our results strongly suggest that IGF-1 inhibits 5-Fu induced apoptosis through increasing survivin levels, which prevents Smac/DIABLO release and blocks the activation of caspases. Therefore, up-regulation of IGF-1 and survivin would seem to be responsible for 5-Fu chemoresistance in esophageal cancer patients and these factors may be the valuable predictors of 5-Fu chemoresistance in esophageal carcinoma.

Magnetic structure, excitations and short-range order in honeycomb Na2Ni2TeO6.

Na2Ni2TeO6has a layered hexagonal structure with a honeycomb lattice constituted by Ni2+and a chiral charge distribution of Na+that resides between the Ni layers. In the present work, the antiferromagnetic (AFM) transition temperature of Na2Ni2TeO6is confirmed atTN≈ 27 K, and further, it is found to be robust up to 8 T magnetic field and 1.2 GPa external pressure; and, without any frequency-dependence. Slight deviations from nominal Na-content (up to 5%) does not seem to influence the magnetic transition temperature,TN. Isothermal magnetization curves remain almost linear up to 13 T. Our analysis of neutron diffraction data shows that the magnetic structure of Na2Ni2TeO6is faithfully described by a model consisting of two phases described by the commensurate wave vectorsk→c,0.500and0.500.5, with an additional short-range order component incorporated in to the latter phase. Consequently, a zig-zag long-range ordered magnetic phase of Ni2+results in the compound, mixed with a short-range ordered phase, which is supported by our specific heat data. Theoretical computations based on density functional theory predict predominantly in-plane magnetic exchange interactions that conform to aJ1-J2-J3model with a strongJ3term. The computationally predicted parameters lead to a reliable estimate forTNand the experimentally observed zig-zag magnetic structure. A spin wave excitation in Na2Ni2TeO6atE≈ 5 meV atT= 5 K is mapped out through inelastic neutron scattering experiments, which is reproduced by linear spin wave theory calculations using theJvalues from our computations. Our specific heat data and inelastic neutron scattering data strongly indicate the presence of short-range spin correlations, atT>TN, stemming from incipient AFM clusters.

Adipocytes promote malignant growth of breast tumours with monocarboxylate transporter 2 expression via ß-hydroxybutyrate.

Adipocytes are the most abundant stromal partners in breast tissue. However, the crosstalk between breast cancer cells and adipocytes has been given less attention compared to cancer-associated fibroblasts. Here we find, through systematic screening, that primary mammary gland-derived adipocytes (MGDAs) promote growth of breast cancer cells that express monocarboxylate transporter 2 (MCT2) both in vitro and in vivo. We show that ß-hydroxybutyrate is secreted by MGDAs and is required to enhance breast cancer cells malignancy in vitro. Consistently, ß-hydroxybutyrate is sufficient to promote tumorigenesis of a mouse xenograft model of MCT2-expressing breast cancer cells. Mechanistically we observe that upon co-culturing with MGDAs or treatment with ß-hydroxybutyrate, breast cancer cells expressing MCT2 increase the global histone H3K9 acetylation and upregulate several tumour-promoting genes. These results suggest that adipocytes promote malignancy of MCT2-expressing breast cancer via ß-hydroxybutyrate potentially by inducing the epigenetic upregulation of tumour-promoting genes.

Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/ß-catenin pathway.

Tumor microenvironment plays a critical role in regulating tumor progression by secreting factors that mediate cancer cell growth. Stromal fibroblasts can promote tumor growth through paracrine factors; however, restraint of malignant carcinoma progression by the microenvironment also has been observed. The mechanisms that underlie this paradox remain unknown. Here, we report that the tumorigenic potential of breast cancer cells is determined by an interaction between the Robo1 receptor and its ligand Slit2, which is secreted by stromal fibroblasts. The presence of an active Slit2/Robo1 signal blocks the translocation of ß-catenin into nucleus, leading to downregulation of c-myc and cyclin D1 via the phosphoinositide 3-kinase (PI3K)/Akt pathway. Clinically, high Robo1 expression in the breast cancer cells correlates with increased survival in patients with breast cancer, and low Slit2 expression in the stromal fibroblasts is associated with lymph node metastasis. Together, our findings explain how a specific tumor microenvironment can restrain a given type of cancer cell from progression and show that both stromal fibroblasts and tumor cell heterogeneity affect breast cancer outcomes.

Multiple lineages of human breast cancer stem/progenitor cells identified by profiling with stem cell markers.

Heterogeneity of cancer stem/progenitor cells that give rise to different forms of cancer has been well demonstrated for leukemia. However, this fundamental concept has yet to be established for solid tumors including breast cancer. In this communication, we analyzed solid tumor cancer stem cell markers in human breast cancer cell lines and primary specimens using flow cytometry. The stem/progenitor cell properties of different marker expressing-cell populations were further assessed by in vitro soft agar colony formation assay and the ability to form tumors in NOD/SCID mice. We found that the expression of stem cell markers varied greatly among breast cancer cell lines. In MDA-MB-231 cells, PROCR and ESA, instead of the widely used breast cancer stem cell markers CD44(+)/CD24(-/low) and ALDH, could be used to highly enrich cancer stem/progenitor cell populations which exhibited the ability to self renew and divide asymmetrically. Furthermore, the PROCR(+)/ESA(+) cells expressed epithelial-mesenchymal transition markers. PROCR could also be used to enrich cells with colony forming ability from MB-361 cells. Moreover, consistent with the marker profiling using cell lines, the expression of stem cell markers differed greatly among primary tumors. There was an association between metastasis status and a high prevalence of certain markers including CD44(+)/CD24(-/low), ESA(+), CD133(+), CXCR4(+) and PROCR(+) in primary tumor cells. Taken together, these results suggest that similar to leukemia, several stem/progenitor cell-like subpopulations can exist in breast cancer.