Adiponectin is a well-known insulin sensitizer and anti-inflammatory molecule, possessing therapeutic potentials in cardiovascular, metabolic and cancer diseases. Results of the present study demonstrate that adiponectin is expressed in a population of regulatory T-cells (Treg) resided within the thymic nurse cell (TNC) complexes. Adoptive transfer of adiponectin-expressing Treg precursors effectively attenuated obesity, improved glucose and insulin tolerance, prevented fatty liver injuries in wild-type mice fed a high-fat diet, and significantly inhibited breast cancer development in MMTV-PyVT transgenic mice. Within the TNC complexes, locally produced adiponectin bound to and regulated the expression as well as the distribution of CD100, a transmembrane lymphocyte semaphorin, in turn modulating the lymphoepithelial interactions to facilitate T-cell development and maturation. In summary, adiponectin plays an important role in the selection and development of T lymphocytes within the TNC complexes. Adiponectin-expressing Treg represent a promising candidate for adoptive cell immunotherapy against obesity-related metabolic and cancer diseases.

Objective The biological functions and molecular mechanisms of miR-935 have been widely investigated in various types of cancer. The aim of the present study was to explore the function of miR-935 in glioma. Methods Bioinformatic analysis and quantitative real-time fluorescent PCR (qRT-PCR) were used to determine the expression of miR-935 in glioma tissues and glioma cell lines. Chi-square test was performed to analyze the relationship between the expression of miR-935 and clinical traits. CCK-8 assay, colony formation assay, cell cycle analysis and subcutaneous tumorigenesis model in nude mice were conducted to determine the effects of miR-935 on the proliferation of glioma cells both in vitro and in vivo. Wound healing and transwell assays were used to detect the effects of miR-935 on the migration and invasion of glioma cells in vitro. The relationship between miR-935 and HIF1α was analyzed using bioinformatics, luciferase reporter assay and Western blotting. Results The expression of miR-935 was lower in glioma tissues than in the adjacent tissues, and in cell lines than in the normal human astrocytes (NHAs), and the low expression levels of miR-935 predicted a poor outcome. Exogenous overexpression of miR-935 inhibited the proliferation of glioma cells both in vitro and in vivo, and suppressed the migration and invasion of glioma cells in vitro. HIF1α was identified as the target of miR-935, whereas miR-935 overexpression decreased the expression of HIF1α and its target genes VEGF, MCL1 and GLUT1. Strikingly, overexpression of HIF1α significantly decreased the expression of miR-935, whereas silencing HIF1α increased the expression of miR-935. Similarly, HIF1α overexpression remarkably reversed the inhibitory effects of miR-935 on the proliferation, migration and invasion of glioma cells. Conclusion Overall, present study reveals the presence of miR-935/HIF1α feedback loop in glioma, which inhibits the development of glioma. This feedback loop may be a potential target for the treatment of glioma.

Cancer development depends on the interactions between epithelial carcinoma cells and the stromal microenvironment. The present study investigated the role of adiponectin, an adipokine with potent tumor‐suppressive activities, in modulating the stromal microenvironment during breast cancer development in mice. Trans‐implantation of the stromal vascular fractions (SVF) of mammary adipose tissue from adiponectin‐deficient MMTV‐PyVT mice promotes the development of MDA‐MB‐231 human breast cancers in NOD/SCID mice, which exhibit the aggressive metaplastic basal epithelial‐like molecular features. In MMTV‐PyVT mammary tumors, adiponectin deficiency significantly decreases the density of CD3+ tumor‐infiltrating lymphocytes and enhances the SVF composition of CD44+/CD25−/CD100+ cells that are originated from thymus. Adiponectin plays an important role in T‐cell development and maturation partly by modulating the epithelial stromal microenvironment of thymus. Adiponectin deficiency prevents the positive selection of CD3+ T‐cells and the negative selection of CD44+CD25−CD100+ T‐cells by thymic nurse cells (TNCs). Thus, reduced production of CD3+ T‐cells as well as enhanced release of CD44+/CD25−/CD100+ cells from thymus into the circulation give rise to a tumor‐permissive microenvironment in mammary tissues of MMTV‐PyVT mice lacking adiponectin. Moreover, CD44+/CD25−/CD100+ cells represent a major metaplastic component contributing to the development of more aggressive basal epithelial‐like mammary tumors in MMTV‐PyVT or NOD/SCID mice implanted with human MDA‐MB‐231 breast cancer cells. Treatment with adiponectin restores thymic T‐cell maturation/selection process and prevents the development of metaplastic basal epithelial‐like breast cancer in MMTV‐PyVT mice. In summary, the present study reveals that adiponectin acts as an immunomodulatory stromal factor in both the thymus and mammary tumor microenvironment to elicit the multifaceted anti‐tumorigenic functions. Support or Funding Information This work was supported in part by grants from Seeding Funds for basic research of the University of Hong Kong, Research Grant Council Grants (17121714, HKU779712M, HKU780613M) of Hong Kong; And the National Basic Research Program of China (973 program 2015CB553603).

Adipose tissue is a pivotal organ determining longevity, due largely to its role in maintaining whole-body energy homeostasis and insulin sensitivity. SIRT1 is a NAD-dependent protein deacetylase possessing antiaging activities in a wide range of organisms. The current study demonstrates that mice with adipose tissue–selective overexpression of hSIRT1(H363Y), a dominant-negative mutant that disrupts endogenous SIRT1 activity, show accelerated development of metabolic aging. These mice, referred to as Adipo-H363Y, exhibit hyperglycemia, dyslipidemia, ectopic lipid deposition, insulin resistance, and glucose intolerance at a much younger age than their wild-type littermates. The metabolic defects of Adipo-H363Y are associated with abnormal epigenetic modifications and chromatin remodeling in their adipose tissues, as a result of excess accumulation of biotin, which inhibits endogenous SIRT1 activity, leading to increased inflammation, cellularity, and collagen deposition. The enzyme acetyl-CoA carboxylase 2 plays an important role in biotin accumulation within adipose tissues of Adipo-H363Y. Calorie restriction prevents biotin accumulation, abolishes abnormal histone biotinylation, and completely restores the metabolic and adipose functions of Adipo-H363Y. The effects are mimicked by short-term restriction of biotin intake, an approach potentially translatable to humans for maintaining the epigenetic and chromatin remodeling capacity of adipose tissues and preventing aging-associated metabolic disorders.

The gold (III) porphyrin complex, gold-2a, elicits anti-tumor activity by targeting the Wnt/β-catenin signaling pathway [Chow KH et al, Cancer Research 2010;70(1):329-37]. Here, the molecular mechanisms underlying the inhibitory effects of this compound on WNT1 gene expression were elucidated further. A response element to gold-2a was identified located within the -1290 to -1112 nt region of the WNT1 promoter, containing a binding site for the transcription regulator Yin Yang 1 (YY1). Gold-2a promoted the association of YY1 and suppressor of zeste 12 (Suz12; a component of the polycomb repressor complex 2) with the WNT1 promoter. Under normal culture conditions, the intracellular translocalization of YY1 was synchronized with cell cycle progression and WNT1 expression. Gold-2a promoted the nuclear accumulation and abolished the nuclear exportation of YY1, resulting in a persistent inhibition of WNT1 expression and a cell cycle arrest at G1/S phase. A dimorphic role of YY1 in regulating cell proliferation and division was revealed. Thus, the present study extends the understanding of the anti-tumor mechanism of gold-2a to the epigenetic level, which involves the modulation of the dynamic interactions between YY1 and a specific region of the WNT1 promoter.

Background: The PI3K-Akt signal pathway plays a key role in tumorigenesis and the development of drug-resistance. Cytotoxic chemotherapy resistance is linked to limited therapeutic options and poor prognosis.Methodology/Principal Findings: Examination of FOXO3a and phosphorylated-Akt (P-Akt) expression in breast cancer tissue microarrays showed nuclear FOXO3a was associated with lymph node positivity (p = 0.052), poor prognosis (p = 0.014), and P-Akt expression in invasive ductal carcinoma. Using tamoxifen and doxorubicin-sensitive and -resistant breast cancer cell lines as models, we found that doxorubicin-but not tamoxifen-resistance is associated with nuclear accumulation of FOXO3a, consistent with the finding that sustained nuclear FOXO3a is associated with poor prognosis. We also established that doxorubicin treatment induces proliferation arrest and FOXO3a nuclear relocation in sensitive breast cancer cells. Induction of FOXO3a activity in doxorubicin-sensitive MCF-7 cells was sufficient to promote Akt phosphorylation and arrest cell proliferation. Conversely, knockdown of endogenous FOXO3a expression reduced PI3K/Akt activity. Using MDA-MB-231 cells, in which FOXO3a activity can be induced by 4-hydroxytamoxifen, we showed that FOXO3a induction up-regulates PI3K-Akt activity and enhanced doxorubicin resistance. However FOXO3a induction has little effect on cell proliferation, indicating that FOXO3a or its downstream activity is deregulated in the cytotoxic drug resistant breast cancer cells. Thus, our results suggest that sustained FOXO3a activation can enhance hyperactivation of the PI3K/Akt pathway.Conclusions/Significance: Together these data suggest that lymph node metastasis and poor survival in invasive ductal breast carcinoma are linked to an uncoupling of the Akt-FOXO3a signaling axis. In these breast cancers activated Akt fails to inactivate and re-localize FOXO3a to the cytoplasm, and nuclear-targeted FOXO3a does not induce cell death or cell cycle arrest. As such, sustained nuclear FOXO3a expression in breast cancer may culminate in cancer progression and the development of an aggressive phenotype similar to that observed in cytotoxic chemotherapy resistant breast cancer cell models.