bims-stacyt Biomed news
on Paracrine crosstalk between cancer and the organism
Issue of 2018‒08‒05
five papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge

  1. Gene. 2018 Jul 25. pii: S0378-1119(18)30842-4. [Epub ahead of print]
    Liu R, Luo Q, You W, Jin M.
      Chronic wounds are a common surgical problem exacerbated by diabetes. A hyperglycemic microenvironment induces inflammation and apoptosis, and plays an important role in vascular endothelial cell dysfunction in diabetes. Increasing evidence shows that high mobility group box 1 (HMGB1) expression is related to inflammation and apoptosis. The aim of this study was to determine the function of HMGB1 in hyperglycemia-induced vascular endothelial cell dysfunction. The results showed that the expression of HMGB1 was increased in human umbilical vein endothelial cells (HUVECs) after exposure to high glucose (25 mM). Downregulation of HMGB1 attenuated the high glucose-induced antiangiogenesis of HUVECs, and the decrease expression of HMGB1 inhibiting HUVEC apoptosis and inflammatory factor expression. In addition, miR-106 expression in HUVECs was decreased under high glucose conditions. Increased miR-106 significantly reversed the high glucose-induced vascular endothelial cell dysfunction by inhibition of HUVEC apoptosis and inflammatory factor expression. However, HMGB1 overexpression attenuated the protective effect of miR-106 on HUVECs in high glucose conditions. This suggested that miR-106 suppressed hyperglycemia-induced vascular endothelial cell dysfunction by targeting HMGB1. Double fluorescent reporter assays confirmed that miR-106 interacted with the 3'-UTR of HMGB1 and inhibited HMGB1 expression. Taken together, these data collectively suggested that miR-106 was a potential molecular target for inhibiting high glucose-induced inflammation and apoptosis by targeting HMGB1.
    Keywords:  Apoptosis; HMGB1; Hyperglycemia; Inflammation; MiR-106
  2. Lipids Health Dis. 2018 Jul 28. 17(1): 178
    Tiao MM, Lin YJ, Yu HR, Sheen JM, Lin IC, Lai YJ, Tain YL, Huang LT, Tsai CC.
      BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) can develop in prenatal stages and can be exacerbated by exposure to a postnatal high-fat (HF) diet. We investigated the protective effects of resveratrol on prenatal and postnatal HF diet-induced NAFLD.METHODS: Male Sprague-Dawley rat offspring were placed in five experimental groups (n = 10-12 per group): normal diet (VNF), maternal HF diet (ONF), postnatal HF diet (VHF), and maternal HF diet/postnatal HF diet (OHF). A therapeutic group with resveratrol for maternal HF diet/postnatal HF diet (OHFR) was used for comparison. Resveratrol (50 mg/kg/day) was dissolved in drinking water for offspring from post-weaning to postnatal day (PND) 120.
    RESULTS: We found that HF/HF-induced NAFLD was prevented in adult offspring by the administration of resveratrol. Resveratrol administration mediated a protective effect on rats on HF/HF by regulating lipid metabolism, reducing oxidative stress and apoptosis, restoring nutrient-sensing pathways by increasing Sirt1 and leptin expression, and mediating the renin-angiotensin system (RAS) to decrease angiotensinogen, renin, ACE1, and AT1R levels and increased ACE2, AT2R and MAS1 levels compared to those in the OHF group.
    CONCLUSION: Our results suggest that a maternal and post-weaning HF diet increases liver steatosis and apoptosis via the RAS. Resveratrol might serve as a therapeutic target by mediating protective actions against NAFLD in offspring exposed to a combination of maternal and postnatal HF diet.
    Keywords:  High-fat diet; Nonalcoholic fatty liver disease (NAFLD); Renin-angiotensin system (RAS); Resveratrol
  3. J Dairy Sci. 2018 Jul 25. pii: S0022-0302(18)30675-1. [Epub ahead of print]
    Mann S, Sipka A, Leal Yepes FA, Nydam DV, Overton TR, Wakshlag JJ.
      Transition dairy cows experience a nutrient deficit, particularly in the immediate postpartum period. At the same time, the inflammatory balance is altered and cows exhibit an immune response primed for inflammatory response rather than tolerance. The mechanistic link that might be underlying the immunological effects due to the lack in nutrients is not fully understood. Studies in other species demonstrate an orchestrating role of nutrient-sensing kinases in the determination of immune phenotypes and immune cell proliferation and differentiation. Our primary objective was to investigate changes in energy storage and signaling through the protein kinase B (AKT)/mechanistic target of rapamycin complex 1 (mTOR) pathway in bovine immune cells in the transition period, as well as the association with cytokine expression profiles. A secondary objective was to test if supplementation with branched-chain amino acids alone or in combination with oral propylene glycol had any effect on the measured parameters. To assess cellular energy storage, glycogen concentration was measured by an enzymatic-fluorometric method in peripheral blood mononuclear cells (PBMC) of multiparous Holstein cows (n = 72) at 3 time points in the transition period (21 d before, 7 and 28 d after calving). At the same time points, phosphorylation of proteins in the AKT/mTOR pathway was assessed by immunoblotting in PBMC from 60 animals. Whole-blood leukocyte cytokine gene expression of IL12B, IL6, IL1B, TNF, and IL10 was measured in samples from 50 animals by reverse-transcription quantitative PCR with and without stimulation of samples with 10 ng/mL of lipopolysaccharide. Compared with glycogen concentration of prepartum PBMC, glycogen concentration decreased by 37% on d 7 postpartum. The activation of AKT/mTOR in bovine PBMC postpartum was reduced compared with prepartum values. Results of reverse-transcription quantitative PCR showed an increase in cytokine gene expression postpartum compared with prepartum values. Supplementation with branched-chain amino acids alone or in combination with oral propylene glycol did not alter glycogen storage, AKT/mTOR activity, or inflammatory balance as assessed by the measured parameters in this study. We conclude that the nutrient deficit of the immediate postpartum period is sensed by bovine immune cells, and that it affects their energy storage as well as cellular signaling pathways postpartum. Temporal associations with changes in cytokine gene expression are intriguing and warrant further investigation of the role of this pathway as a possible link between metabolism and immune phenotype postpartum.
    Keywords:  AKT kinase; inflammation; mTOR kinase; transition
  4. Exp Cell Res. 2018 Jul 26. pii: S0014-4827(18)30587-1. [Epub ahead of print]
    Yan B, Jiang Z, Cheng L, Chen K, Zhou C, Sun L, Qian W, Li J, Cao J, Xu Q, Ma Q, Lei J.
      Pancreatic stellate cells (PSCs), a pivotal component of the tumor microenvironment, contribute to tumor growth and metastasis. PSC-derived factors are essential for triggering the generation and maintenance of cancer stem cells (CSCs). However, the mechanisms by which paracrine signals regulate CSC-like properties such as glycolytic metabolism have not been fully elucidated. Here, we report that two pancreatic cancer cell lines, Panc-1 and MiaPaCa-2, reacted differently when treated with hepatocyte growth factor (HGF) secreted from PSCs. MiaPaCa-2 cells showed little response with regard to CSC-like properties after HGF treatment. We have shown that in Panc-1 cells by activating its cognate receptor c-MET, paracrine HGF resulted in YAP nuclear translocation and HIF-1α stabilization, thereby promoting the expression of CSC pluripotency markers NANOG, OCT-4 and SOX-2 and tumor sphere formation ability. Furthermore, HGF/c-MET/YAP/HIF-1α signaling enhanced the expression of Hexokinase 2 (HK2) and promoted glycolytic metabolism, which may facilitate CSC-like properties. Collectively, our study demonstrated that HGF/c-MET modulates tumor metabostemness by regulating YAP/HIF-1α and may hold promise as a potential therapeutic target against pancreatic cancer.
    Keywords:  HGF/c-MET; HIF-1α; YAP; cancer stem cells; glycolysis; pancreatic stellate cells
  5. Diabetes Res Clin Pract. 2018 Jul 26. pii: S0168-8227(18)30282-1. [Epub ahead of print]
    Dworacka M, Iskakova S, Wesołowska A, Zharmahanova G, Stelmaszyk A, Frycz BA, Jagodziński PP, Dworacki G.
      AIM: Over the last few years, studies have indicated that fluctuant hyperglycemia is very likely to increase the risk of cardiovascular complications of diabetes. Statins are widely used in diabetes for the prevention of cardiovascular complications, but it is still not clear whether simvastatin could also prevent glycaemic variability - induced aberrant angiogenesis which plays a significant role in the development of atherosclerosis.METHODS: Wistar rats were divided into four groups: 1) simvastatin-treated (20 mg/kg for 8 consecutive weeks) type 2 diabetes rat model with daily glucose excursions, 2) placebo-treated type 2 diabetes rat model with daily glucose excursions, 3) placebo-treated stable well-controlled type 2 diabetes rat model and 4) placebo-treated non-diabetic rats. Daily glucose fluctuations and several angiogenic factors: cVEGF, mRNA VEGF, VEGF-R1, VEGF-R2, TGF-beta expression, circulating endothelial and progenitor endothelial cells were measured in all groups.
    RESULTS: Simvastatin decreased several factors enhanced by glucose excursions: circulating VEGF, mRNA TGF-beta expression in the myocardium and mRNA VEGFR-2 expression in the aorta. Simvastatin increased some factors attenuated by glucose fluctuations: mRNA VEGF expression and mRNA VEGFR-1 expression in the myocardium and in the aorta. In the simvastatin-treated group with glycaemic variability, the percentage of circulating endothelial cells was lower and the percentage of progenitor endothelial cells in peripheral blood was higher than in the placebo-treated rats with glucose-fluctuations.
    CONCLUSIONS: Simvastatin used in the rat model of type 2 diabetes with glucose variability reduces glucose variability and limits glucose fluctuations-induced changes in the expression of angiogenic factors in the cardiovascular system.
    Keywords:  angiogenic factors; diabetes complication; glucose variability; simvastatin