No abstract

Hypoxia is a common feature of solid tumors and is associated with aggressiveness and poor patient outcomes. Exosomes, initially considered to be cellular "garbage dumpsters," are now implicated in mediating interactions with the cellular environment. However, the mechanisms underlying the association between exosomes and hypoxia during cancer progression remain poorly understood. In this study, we found that exosomes derived from hypoxic oral squamous cell carcinoma (OSCC) cells increased the migration and invasion of OSCC cells in a HIF1a and HIF-2a-dependent manner. Given that exosomes have been shown to transport miRNAs to alter cellular functions, we performed miRNA sequencing of normoxic and hypoxic OSCCderived exosomes. Of the 108 miRNAs that were differentially expressed, miR-21 stood out as one of the most significantly upregulated miRNAs under hypoxic conditions. miR-21 depletion in hypoxic OSCC cells led to decreased miR-21 levels in exosomes and significantly reduced cell migration and invasion. Conversely, restoration of miR-21 expression in HIF-1a and HIF2a-depleted exosomes rescued OSCC cell migration and invasion. Moreover, exosomal miR-21 markedly enhanced snail and vimentin expression, while significantly decreasing E-cadherin levels in OSCC cells, in vitro and in vivo. Finally, circulating exosomal miR-21 levels were closely associated with HIF-1a/ HIF-2a expression, T stage, and lymph node metastasis in patients with OSCC. In conclusion, our findings suggest that the hypoxic microenvironment may stimulate tumor cells to generate miR-21-rich exosomes that are delivered to normoxic cells to promote prometastatic behaviors and prompt further investigation into the therapeutic value of exosome inhibition for cancer treatment.

A foundation of the modern technology that uses single-crystal silicon has been the growth of high-quality single-crystal Si ingots with diameters up to 12 inches or larger. For many applications of graphene, large-area high-quality (ideally of single-crystal) material will be enabling. Since the first growth on copper foil a decade ago, inch-sized single-crystal graphene has been achieved. We present here the growth, in 20 minutes, of a graphene film of 5 50 cm 2 dimension with > 99% ultra-highly oriented grains. This growth was achieved by: (i) synthesis of sub-metre-sized single-crystal Cu (111) foil as substrate; (ii) epitaxial growth of graphene islands on the Cu(111) surface; (iii) seamless merging of such graphene islands into a graphene film with high single crystallinity and (iv) the ultrafast growth of graphene film. These achievements were realized by a temperature-driven annealing technique to produce single-crystal Cu(111) from industrial polycrystalline Cu foil and the marvellous effects of a continuous oxygen supply from an adjacent oxide. The as-synthesized graphene film, with very few misoriented grains (if any), has a mobility up to ~ 23,000 cm 2 V -1 s -1 at 4 K and room temperature sheet resistance of ~ 230 □ ⁄ . It is very likely that this approach can be scaled up to achieve exceptionally large and highquality graphene films with single crystallinity, and thus realize various industrial-level applications at a low cost.

No abstract

A hypoxic microenvironment plays important roles in the progression of solid tumors, including oral squamous cell carcinoma (OSCC). Long noncoding RNAs (lncRNAs) have gained much attention in the past few years. However, it is not clear whether lncRNAs can regulate hypoxia adaptation of OSCC or which lncRNAs participate in this process. Using a lncRNA microarray, we analyzed the aberrant lncRNA expression profiles in OSCC tissues compared with paired normal oral mucosa and in hypoxic OSCC cells compared with normoxic OSCC cells. The top 10 lncRNAs that had more than threefold increase with P‐value <0.01 in both microarray data were validated by qRT‐PCR. Among the top 10 lncRNAs, hyaluronan synthase 2 antisense 1 (HAS2‐AS1) was the only one that has a hypoxia‐responsive element (HRE) on its promoter region and has been validated to increase in OSCC tissues and in cells cultured under hypoxia. Tumor HAS2‐AS1 levels were closely associated with lymph node metastasis and hypoxic tumor status in patients with OSCC. Moreover, the hypoxia‐induced HAS2‐AS1 expression is dependent on HIF‐1α which directly binds to and activates the transcription of HAS2‐AS1. In addition, HAS2‐AS1 mediates hypoxia‐induced epithelial mesenchymal transition of OSCC cells via stabilizing HAS2. In conclusion, our results suggest that hypoxia would induce an overexpression of HAS2‐AS1 in an HIF‐1α dependent manner. The increase of HAS2‐AS1 plays important roles mediating the hypoxia‐regulated EMT and invasiveness of OSCC.

CUEDC2, a CUE-domain-containing protein, modulates inflammation, but its involvement in tumorigenesis is still poorly understood. Here, we report that CUEDC2 is a key regulator of macrophage function and critical for protection against colitis-associated tumorigenesis. CUEDC2 expression is dramatically upregulated during macrophage differentiation, and CUEDC2 deficiency results in excessive production of proinflammatory cytokines. The level of CUEDC2 in macrophages is modulated by miR- 324-5p. We find that Cuedc2 KO mice are more susceptible to dextran-sodium-sulfate-induced colitis, and macrophage transplantation results suggest that the increased susceptibility results from the dysfunction of macrophages lacking CUEDC2. Furthermore, we find that Cuedc2 KO mice are more prone to colitis-associated cancer. Importantly, CUEDC2 expression is almost undetectable in macrophages in human colon cancer, and this decreased CUEDC2 expression is associated with high levels of interleukin-4 and miR-324-5p. Thus, CUEDC2 plays a crucial role in modulating macrophage function and is associated with both colitis and colon tumorigenesis.

In this study, we sought to investigate the potential application of γδ T cell-derived extracellular vesicles (γδTDEs) as drug delivery system (DDS) for miR-138 in the treatment of oral squamous cell carcinoma (OSCC). Our data showed that overexpression of miR-138 in γδ T cells obtained miR-138-rich γδTDEs accompanying increased expansion and cytotoxicity of γδ T cells. γδTDEs inherited the cytotoxic profile of γδ T cells and could efficiently deliver miR-138 to OSCC cells, resulting in synergetic inhibition on OSCC both in vitro and in vivo. The pre-immunization by miR-138-rich γδTDEs inhibited the growth of OSCC tumors in immunocompetent C3H mice, but not in nude mice, suggesting an immunomodulatory role by miR-13-rich γδTDEs. γδTDEs and miR-138 additively increased the proliferation, interferon-γ (IFN-γ) production, and cytotoxicity of CD8+ T cells against OSCC cells. Only delivered by γδTDEs can miR-138 efficiently target programmed cell death 1 (PD-1) and CTLA-4 in CD8+ T cells. We conclude that γδTDEs delivering miR-138 could achieve synergetic therapeutic effects on OSCC, which is benefited from the individual direct anti-tumoral effects on OSCC and immunostimulatory effects on T cells by both γδTDEs and miR-138; γδTDEs could serve as an efficient DDS for microRNAs (miRNAs) in the treatment of cancer.

Aim: The aim of this study is to explore the relationship between the neutrophil-to-lymphocyte ratio (NLR) and clinicopathological features in patients with papillary thyroid carcinoma (PTC). Methods: We performed an analysis of 843 patients, including 321 patients with PTC, 83 patients with thyroid adenoma and 439 patients with nodular goiter (NG). Thyroglobulin and thyrotropin were measured in each patient. Neutrophils, lymphocytes, and platelets were counted. Statistical analysis was used to correlate the NLR with demographic and histopathologic characteristics of the patients. Result: Age correlated with NLR and lymphocyte number in patients with PTC and NG. In patients aged >45 years, those with PTC had a higher NLR and a lower lymphocyte count than those with NG. Patients with PTC aged <45 years had a higher leukocyte count and a lower NLR than those aged ≥45 years. Patients with clinical stage I/II PTC had a lower NLR and a higher lymphocyte count than patients with stage III/IV. Conclusions: Younger patients with PTC had a higher lymphocyte count but a lower NLR than older patients with PTC. The NLR and lymphocyte counts were associated with the clinical stage. Thus, a higher NLR and a lower lymphocyte count may be prognostic for stratifying patients with thyroidal goiters and are risk factors of PTC for older patients.