Inhibition of the prolyl isomerase Pin1 enhances the ability of sorafenib to induce cell death and inhibit tumor growth in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the sixth most common cancer, but is the second leading cause of cancer deaths, partially due to its heterogeneity and drug resistance. Sorafenib is the only medical treatment with a proven efficacy against advanced HCC, but its overall clinical efficacy is still modest. Therefore, a major challenge is how to improve its therapeutic efficacy. The unique prolyl isomerase Pin1 regulates numerous cancer-driving pathways. Notably, Pin1 is overexpressed in about 70% HBV-positive HCC patients and contributes to HCC tumorigenesis. However, the role of Pin1 in the efficacy of sorafenib against HCC is unknown. Here we found that sorafenib down-regulated Pin1 mRNA and protein expression, likely through inhibition of Pin1 transcription by the Rb/E2F pathway. Importantly, Pin1 knockdown potently enhanced the ability of sorafenib to induce cell death in HCC, which was further supported by the findings that Pin1 knockdown led to stabilization of Fbxw7 and destabilization of Mcl-1. Furthermore, all-trans retinoic acid (ATRA), a known anticancer drug that inhibits and ultimately induces degradation of active Pin1 in cancer cells, also potently sensitized HCC cells to sorafenib-induced cell death at least in part through a caspase-dependent manner. Moreover, ATRA also synergistically enhanced the ability of sorafenib to reduce Pin1 and inhibit tumor growth of HCC in mouse xenograft models. Collectively, these results not only demonstrate that Pin1 down-regulation is a key event underlying the anti-tumor effects of sorafenib, but also uncover that Pin1 inhibitors offer a novel approach to enhance the therapeutic efficacy of sorafenib against HCC

Ammonia oxidizers and denitrifiers in response to reciprocal elevation translocation in an alpine meadow on the Tibetan Plateau

Purpose: Global climate change, in particular temperature variation, is likely to alter soil microbial abundance and composition, with consequent impacts on soil biogeochemical cycling and ecosystem functioning. However, responses of belowground nitrogen transformation microorganisms to temperature changes in high-elevation terrestrial ecosystems are not well understood. Materials and methods: Here, the effects of simulated cooling and warming on the abundance and community composition of ammonia-oxidizing archaea (AOA) and bacteria (AOB), as well as the abundance of denitrifiers, were investigated using quantitative polymerase chain reaction and clone library approaches, on the basis of a 2-year reciprocal elevation translocation experiment along an elevation gradient from 3,200 to 3,800 m above sea level on the Tibetan Plateau. Results and discussion: We found that, compared with the temperature variations caused by elevation translocation, the soil origin exerted a much stronger influence on AOA abundance. There were significant effects of both soil origin and elevation translocation on AOB abundance, which was particularly decreased by elevation-enhanced (simulated cooling) and increased by elevation-decreased (simulated warming) treatments. Altered temperature affected the abundance of nirK rather than nirS and nosZ genes, and the latter two seemed to be associated tightly with the soil origin. Furthermore, the results showed that temperature changes had obvious influences on the community structure and diversity of AOB, but not AOA. More apparent response of AOB to warming than in other studies on grassland and forest ecosystems may be attributed to higher elevation and lower mean annual temperature in this study. Conclusions: Our findings thus suggest that, in comparison with AOA and denitrifying populations, AOB may respond more sensitively to natural temperature variation caused by elevation translocation in this alpine grassland ecosystem on the Tibetan Plateau

Methane emission by plant communities in an alpine meadow on the Qinghai-Tibetan Plateau: a new experimental study of alpine meadows and oat pasture

Recently, plant-derived methane (CH4) emission has been questioned because limited evidence of the chemical mechanism has been identified to account for the process. We conducted an experiment with four treatments (i.e. winter-grazed, natural alpine meadow; naturally restored alpine meadow eight years after cultivation; oat pasture and bare soil without roots) during the growing seasons of 2007 and 2008 to examine the question of CH4 emission by plant communities in the alpine meadow. Each treatment consumed CH4 in closed, opaque chambers in the field, but two types of alpine meadow vegetation reduced CH4 consumption compared with bare soil, whereas oat pasture increased consumption. This result could imply that meadow vegetation produces CH4. However, measurements of soil temperature and water content showed significant differences between vegetated and bare soil and appeared to explain differences in CH4 production between treatments. Our study strongly suggests that the apparent CH4 production by vegetation, when compared with bare soil in some previous studies, might represent differences in soil temperature and water-filled pore space and not the true vegetation sources of CH4

MicroRNA-140-5p inhibits hepatocellular carcinoma by directly targeting the unique isomerase Pin1 to block multiple cancer-driving pathways

Hepatocellular carcinoma (HCC) is the second leading cause of cancer related-death. As a major common regulator of numerous cancer-driving pathways and a unique therapeutic target, the prolyl isomerase Pin1 is overexpressed in a majority of HCCs, whereas the mechanism underlying Pin1 overexpression remains elusive. Here we find that miR-140-5p inhibits HCC by directly targeting Pin1 to block multiple cancer-driving pathways. Bioinformatics analysis, miRNA binding and functional assays identify that miR-140-5p directly interacts with the 3′UTR of Pin1 and inhibits Pin1 translation. Furthermore, like stable Pin1 knockdown, moderate overexpression of miR-140-5p not only eliminates Pin1, but also inhibits cells growth and metastasis. Importantly, these effects of miR-140-5p are largely rescued by reconstitution of Pin1. Moreover, miR-140-5p inhibits multiple Pin1-dependent cancer pathways and suppresses tumor growth in mice. The clinical significance of these findings has been substantiated by the demonstrations that miR-140-5p is frequently down-regulated and inversely correlated with Pin1 overexpression in HCC tissues and cell lines. Given prevalent miR-140-5p downregulation in other cancers and major impact of Pin1 overexpression on activating numerous cancer-driving pathways including global miRNA downregulation, the miR-140-5p/Pin1 axis may play a major role in tumorigenesis and offer promising therapeutic targets for HCC and other cancers

Plant species composition under reciprocal transplantion along elevation gradient

The data file is how response of plant species to warming and cooling when reciprocal transplantion along 3200-3800 m elevation gradient form 2007 to 2015 on the Tibetan Plateau

Data from: Richness of plant communities plays a larger role than climate in determining responses of species richness to climate change

1. Experimental warming in situ suggests that warming could lead to a loss of biodiversity. However, species that remain in situ and experience climate change will interact with species tracking climate change, which could also affect patterns of biodiversity. The relative contribution of species gains and losses to net changes in species richness is still unclear. 2. We use transplanted plant communities to test the hypothesis that both the change in climate and ecological communities tracking climate change will influence how species richness responds to climate change. Three intact alpine plant communities were reciprocally transplanted to create scenarios in which species experienced warmer and wetter conditions (transferred to lower elevations) and cooler and drier conditions (transferred to higher elevations) over 10 years on the Tibetan Plateau. Communities transplanted into the same elevation as controls represent species tracking climate change. 3. Transferring to lower elevations generally caused a net increase in richness and a higher rate of gains relative to the control plots; the magnitude of this effect depended on the specific elevation. Transferring to higher elevations lead to either net increases or decreases in richness and gains, depending on elevation. Species gains predicted much more variation in changes in species richness (50%) than did species loss (9%). 4. Species richness at the receptor site and the donor site were both important predictors of variation in species richness, and the abiotic environment did not explain additional variation. Changes in cover of dominant plant species in response to transfers did not predict changes in species richness, species gain, or species loss. Our results suggest that species gains from species tracking climate change at the receptor sites, rather than species loss from the donor sites, predicted changes in species richness. 5. Synthesis. Warming experiments with physical barriers to dispersal may overestimate the negative effect of warming on plant diversity by not accounting for species gains. Our study highlights the importance of biotic factors in addition to the abiotic environment, when considering how climate change will affect plant diversity

Appendix B. Figures showing dynamics of rainfall and air temperature, mean soil temperature and soil moisture at 10 cm, mean frequency and coverage of different plant species during the 5-year experiment under warming and grazing treatments, and aboveground net primary production of natural alpine Kobresia meadow and an annual oat crop under nitrogen fertilization.

Figures showing dynamics of rainfall and air temperature, mean soil temperature and soil moisture at 10 cm, mean frequency and coverage of different plant species during the 5-year experiment under warming and grazing treatments, and aboveground net primary production of natural alpine Kobresia meadow and an annual oat crop under nitrogen fertilization

Appendix A. Tables showing statistical results for aboveground net primary production (ANPP) and dynamics of species composition changed under warming and grazing treatments from 2006 and 2010.

Tables showing statistical results for aboveground net primary production (ANPP) and dynamics of species composition changed under warming and grazing treatments from 2006 and 2010

Grazing intensifies degradation of a Tibetan Plateau alpine meadow through plant-pest interaction

Understanding the plant-pest interaction under warming with grazing conditions is critical to predict the response of alpine meadow to future climate change. We investigated the effects of experimental warming and grazing on the interaction between plants and the grassland caterpillar Gynaephora menyuanensis in an alpine meadow on the Tibetan Plateau in 2010 and 2011. Our results showed that grazing significantly increased nitrogen concentration in graminoids and sward openness with a lower sward height, sward coverage, and plant litter mass in the community. Grazing significantly increased G.menyuanensis body size and potential fecundity in 2010. The increases in female body size were about twofold greater than in males. In addition, grazing significantly increased G.menyuanensis density and its negative effects on aboveground biomass and graminoid coverage in 2011. We found that G.menyuanensis body size was significantly positively correlated with nitrogen concentration in graminoids but negatively correlated with plant litter mass. Even though warming did not significantly increased G.menyuanensis performance and the negative effects of G.menyuanensis on alpine meadow, the increases in G.menyuanensis growth rate and its negative effect on aboveground biomass under the warming with grazing treatment were significantly higher than those under the no warming with grazing treatment. The positive effects of grazing on G.menyuanensis performance and its damage were exacerbated by the warming treatment. Our results suggest that the fitness of G.menyuanensis would increase under future warming with grazing conditions, thereby posing a greater risk to alpine meadow and livestock production