Prognostic value and immune cell infiltration of hypoxic phenotype-related gene signatures in glioblastoma microenvironment.

Glioblastoma (GBM) is a malignant intracranial tumour with the highest proportion and lethality. It is characterized by invasiveness and heterogeneity. However, the currently available therapies are not curative. As an essential environmental cue that maintains glioma stem cells, hypoxia is considered the cause of tumour resistance to chemotherapy and radiation. Growing evidence shows that immunotherapy focusing on the tumour microenvironment is an effective treatment for GBM; however, the current clinicopathological features cannot predict the response to immunotherapy and provide accurate guidance for immunotherapy. Based on the ESTIMATE algorithm, GBM cases of The Cancer Genome Atlas (TCGA) data set were classified into high- and low-immune/stromal score groups, and a four-gene tumour environment-related model was constructed. This model exhibited good efficiency at forecasting short- and long-term prognosis and could also act as an independent prognostic biomarker. Additionally, this model and four of its genes (CLECL5A, SERPING1, CHI3L1 and C1R) were found to be associated with immune cell infiltration, and further study demonstrated that these four genes might drive the hypoxic phenotype of perinecrotic GBM, which affects hypoxia-induced glioma stemness. Therefore, these might be important candidates for immunotherapy of GBM and deserve further exploration.

ZCCHC10 suppresses lung cancer progression and cisplatin resistance by attenuating MDM2-mediated p53 ubiquitination and degradation.

The activation of p53 tumor suppressor is essential for preventing abnormal cell proliferation and carcinogenesis. ZCCHC10 was previously identified as a potential p53-interacting partner in a yeast two-hybrid screen, but the interaction in cells and its subsequent influence on p53 activity and cancer development have not been investigated. In this paper, we demonstrate that ZCCHC10 expression levels are statistically lower in lung adenocarcinoma tissues than the corresponding adjacent noncancerous tissues, and decreased expression of ZCCHC10 mRNA predicts poorer survival of the patients. Ectopic expression of ZCCHC10 in lung cancer cells harboring wild-type p53 dramatically suppresses cell proliferation, colony formation, migration, invasion and cisplatin resistance in vitro, as well as tumor growth and metastasis in vivo. Conversely, knockdown of ZCCHC10 exerts opposite effects in the normal lung cell Beas-2b. However, ZCCHC10 has no influence on the biological behaviors of p53-null (H358) or p53-mutant (H1437) lung cancer cells. Mechanistically, ZCCHC10 binds and stabilizes p53 by disrupting the interaction between p53 and MDM2. The p53 inhibitor pifithrin-α attenuated the influences of ZCCHC10 overexpression on p53 pathway, cell cycle, apoptosis, and epithelial-mesenchymal transition, whereas the p53 activator Nutlin3 could reverse the effects of ZCCHC10 knockdown. Collectively, our results indicate that ZCCHC10 exerts its tumor-suppressive effects by stabilizing the p53 protein and can be used a potential prognostic marker and therapeutic target in lung adenocarcinoma.

CK2-mediated CCDC106 phosphorylation is required for p53 degradation in cancer progression.

BACKGROUND: Dysfunction of p53 is a key cause of cancer development, while CCDC106 can reduce p53 stability and is associated with lung cancer. However, the roles of CCDC106 in other cancer types and its upstream regulators have not been investigated. METHODS: The phosphorylation status was investigated by in vitro kinase assay and Western blotting using phosphorylation-specific antibodies. Co-immunoprecipitation assay and GST-pulldown were used to detect protein interaction. Cell viability, apoptosis, colony formation, wound-healing and invasion assays were measured for in vitro functional analyses. The in vivo effect of CCDC106 on tumor growth was investigated using a subcutaneous xenograft tumor mouse model. RESULTS: We demonstrated that CCDC106 knockdown enhanced apoptosis by stabilizing p53 and suppressed cell viability, colony formation, migration and invasion in cervical cancer HeLa and breast cancer MCF7 cells with wild-type p53 (wtp53), whereas CCDC106 overexpression exerted the opposite effects in normal breast epithelial HBL100 and cervical cancer SiHa cells with wtp53. However, CCDC106 had no similar effects on p53-mutant cervical and breast cancer cells (C33A and MDA-MB-231). Further study showed that CK2 interacts with CCDC106 through its regulatory ß subunit and then phosphorylates CCDC106 at Ser-130 and Ser-147. The phosphorylation of CCDC106 at Ser-130 and Ser-147 is required for its interaction with p53 and nuclear localization, respectively. Inhibiting CCDC106 phosphorylation by substituting both Ser-130 and Ser-147 with alanine or treating cells with the CK2 inhibitor CX-4945 abrogated CCDC106-induced p53 degradation and its oncogenic function in cells with wtp53. Wildtype CCDC106, but not Ser-130/- 147 mutant CCDC106, enhanced tumor growth and p53 degradation in a xenograft mouse model. Moreover, suppression of CCDC106 increased CX-4945 sensitivity of cancer cells with wtp53. CONCLUSION: This study revealed a CK2/CCDC106/p53 signaling axis in the progression of breast and cervical cancers, which may provide a new therapeutic target for cancer treatment.

Effects of extracellular polymeric substances on granulation of anoxic sludge in sequencing batch reactor.

Variations of extracellular polymeric substances (EPS) and its components with sludge granulation were examined in a lab-scale sequencing batch reactor (SBR) which was fed with sodium nitrate and sodium acetate. Ultrasonication plus cation exchange resin (CER) were used as the EPS extraction method. Results showed that after approximately 90 d cultivation, the sludge in the reactor was almost granulated. The content of extracellular polysaccharides increased from 10.36 mg/g-VSS (volatile suspended solids) at start-up with flocculent sludge to 23.18 mg/g-VSS at 91 d with matured granular sludge, while the content of extracellular proteins were almost unchanged. Polysaccharides were the major components of EPS in anoxic granular sludge, accounting for about 70.6-79.0%, while proteins and DNA accounted for about 16.5-18.9% and 4.6-9.9%, respectively. It is proposed that EPS play a positive role in anoxic sludge granulation and polysaccharides might be strongly involved in aggregation of flocs into granules.

[Insulin sensitivity and pancreatic beta cell function changes during the transformation from normal to impaired glucose tolerance].

OBJECTIVE: To investigate the roles of insulin sensitivity and pancreatic beta cell function in the pathogenesis of type 2 diabetes. METHODS: 70 subjects were recruited in a 3-year prospective study. During this period 9 subjects progressed from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) (progressing group), 45 remained same (remaining group) and 16 improved from IGT to NGT (improving group). Acute insulin secretion response (AIR(3 - 5)) during intravenous glucose tolerance test (IVGTT) was adopted to indicate the first phase insulin secretion with the ratio of insulin change from 0 min to 30 min to that of blood glucose from 0 min to 30 min (DeltaI(30)/DeltaG(30)) as the indicator of early insulin secretion and insulin sensitivity (ISI) was analyzed by the formula suggested by Cederholm during oral glucose tolerance (OGTT). RESULTS: (1) For AIR(3 - 5), there were no differences of the baseline level and the 3-year follow-up state between the progressing group and remaining group; neither there were differences between the baseline level and the 3-year follow-up state in both groups. Meanwhile, in the improving group, AIR(3 - 5) increased after the 3-year follow-up time as compared with that at the baseline, but without significance. (2) For DeltaI(30)/DeltaG(30), there were no differences of the baseline level and the follow-up state between the progressing group and remaining group; neither there were differences between the progressing group and remaining group baseline level and the 3-year follow-up state in both groups. Meanwhile, in the improving group, there was no difference between that at baseline and at the follow-up. (3) For ISI, although there was no significant difference between the progressing group and remaining group at the baseline level, yet that at the 3-year follow-up state was different between the progressing group and remaining group with ISI in the progressing group decreased significantly; ISI in improving group increased significantly at the 3-year follow-up state as compared with that at the baseline level and there was significant difference between that in progressing group and remaining group at the 3-year follow-up state. (4) Only ISI, but neither AIR(3 - 5) nor DeltaI(30)/DeltaG(30), had effect on the change of glucose tolerance by logistic regressive analysis. CONCLUSIONS: The ISI was the main change during the progress of NGT to IGT and the improvement of IGT to NGT, indicating that during the early progressive stage of type 2 diabetes, insulin sensitivity (insulin resistance) may play an important role.