Boric acid and Borax Supplementation Reduces Weight Gain in Overweight Rats and Alter L-Carnitine and IGF-I Levels.

The aim of this study was to investigate the effects of boric acid (BA) and borax (BX) on live weight and obesity associated molecules including leptin, L-carnitine, insulin-like growth factor 1 (IGF-I), and heat shock proteins 70 (HSP70) in rats fed with high-fat diet. A total of 60 rats were equally allocated as ND (normal diet), HF (high-fat diet), HF+BA, HF+BX, ND+BX, ND+BA. Body weight increases in HF+BA (85 g) and HF+BX (86 g) were significantly lower (p<0.05) compared to HF group (126 g). Boron treatment decreased serum L-carnitine level in high-fat diet (HF+BA 11.12 mg/L, HF+BX 10.51 mg/L, p<0.05) compared to HF group (15.57 mg/L), while no change was observed in groups ND+BA (7.55 mg/L) and ND+BX (7.57 mg/L) compared to group ND (8.29 mg/L). Neither BA nor BX supplementation in ND and HF groups altered the serum levels of HSP70 and leptin. BA and BX supplementation in rats fed HF resulted in a significant reduction in live weight. Boron compounds altered L-carnitine and IGF-1 levels in rats. These results indicate that boron compounds are beneficial in the treatment of obesity as well as in the prevention of high-fat diet-induced weight increase. Alterations in serum L-carnitine and IGF-1 levels in boron treated rats also indicate possible role of boron compounds in energy metabolism in response to high fat diet.

The protective role of jervine against radiation-induced gastrointestinal toxicity.

In this study, we investigated whether jervine (J) could prevent gastrointestinal (GI) side effects of abdominopelvic radiotherapy (RT) in Wistar-Albino female rats. Rats were divided into five groups: control (C), J only (J), J administered at 5 mg/kg/days for 7 days, RT only (RT), J before RT (J + RT), J administered for seven days before RT, J both before and after RT (J + RT + J), and J administered for 7 days before RT and after RT for 3 days. The weights of rats were measured on the 1st, 7th, and 10th days of the study. Rats were sacrificed to obtain tissues from the liver and intestine, which was followed by taking blood samples intracardially. In addition, the tissues were stained with pyruvate dehydrogenase (PDH) immunohistochemically. In our study, J supplementation markedly reduced weight loss, and histopathological, immunohistochemical, biochemical results suggest that J had a protective effect on GI toxicity following RT.

Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress.

Genetic deletion of the mitochondrial deacetylase sirtuin-3 (Sirt3) results in increased mitochondrial superoxide, a tumor-permissive environment, and mammary tumor development. MnSOD contains a nutrient- and ionizing radiation (IR)-dependent reversible acetyl-lysine that is hyperacetylated in Sirt3⁻/⁻ livers at 3 months of age. Livers of Sirt3⁻/⁻ mice exhibit decreased MnSOD activity, but not immunoreactive protein, relative to wild-type livers. Reintroduction of wild-type but not deacetylation null Sirt3 into Sirt3⁻/⁻ MEFs deacetylated lysine and restored MnSOD activity. Site-directed mutagenesis of MnSOD lysine 122 to an arginine, mimicking deacetylation (lenti-MnSOD(K122-R)), increased MnSOD activity when expressed in MnSOD⁻/⁻ MEFs, suggesting acetylation directly regulates function. Furthermore, infection of Sirt3⁻/⁻ MEFs with lenti-MnSOD(K122-R) inhibited in vitro immortalization by an oncogene (Ras), inhibited IR-induced genomic instability, and decreased mitochondrial superoxide. Finally, IR was unable to induce MnSOD deacetylation or activity in Sirt3⁻/⁻ livers, and these irradiated livers displayed significant IR-induced cell damage and microvacuolization in their hepatocytes.

Distribution of OCPs and PCBs in Mussels (Mytilus galloprovincialis) from the Marmara Sea Coastal Sites.

Mussel samples were collected monthly between October-2010 and October-2011 from four stations (Bosphorus, Bandirma, Gelibolu, Tekirdag) in the Marmara Sea. Two consecutive months' samples were homogenized and combined as a single group for analysis. Mussel samples were analyzed for Organochlorine pesticides (OCPs); (total-DDT, total-HCH, Endrin, α-Endosulfan, ß-Endosulfan, Heptachlor) and Polychlorinated biphenyls (PCBs); (PCB 28, PCB 52, PCB 138, PCB 153, and PCB 180). All analyses were done according to Eurofins house method in ERGO Laboratory in Germany. Concentrations of α-endosulfan and heptachlor in mussel tissues were below method detection limits. The annual average OCPs concentrations among the stations ranged between 0.02 and 1.45 ng/g (wet weight), 1.9-99.75 ng/g (lipid weight) whereas the annual average PCBs concentrations among the stations ranged between 0.03 and 0.40 ng/g (wet weight), 1.71-26.48 ng/g (lipid weight), respectively. There was no relation between fat content of mussels and residues of the contaminants. PCB 138 and PCB 153 were the most predominant PCBs, while total-DDT and total-HCH were the most predominant OCPs in the mussels. Total-DDT concentrations were higher compared to total-HCH and PCBs isomers. Measured levels were below the national and international committees' and institutions' limits for human consumption and protection of aquatic biota.

Activin and TGFß use diverging mitogenic signaling in advanced colon cancer.

BACKGROUND: Understanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFß or activin-induced metastatic phenotype of colon cancer. METHOD: Mitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) -/- or wild type mice. Colon cancer cell lines (+/- SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays. RESULTS: In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFß/MEK/ERK pathway activation. Activin, but not TGFß, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFß increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFß induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling. CONCLUSION: Although activin and TGFß share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFß ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFß family receptors.

Evaluation of biotoxins and toxic metal risks in mussels from the Sea of Marmara following marine mucilage.

The mucilage phenomenon observed in the Sea of Marmara in 2021, has raised public concern about seafood safety. Mediterranean mussels serve as a vehicle in food chain, enabling the transfer of pollutants. Farmed and wild mussels were collected from 4 different stations throughout the fishing season. Biotoxins causing amnesic, paralytic, or diarrhetic shellfish poisonings (ASP, PSP, or DSP) were examined during monthly samplings. Potential health risks posed by cadmium, lead and arsenic were assessed. Health risks were evaluated considering 150 g/week mussel consumption, accounting for the different age groups of consumers (50, 60, 70 kg). Estimated Weekly Intake calculations of metals were determined to be lower than Provisional Tolerable Weekly Intake at all age groups throughout the sampling period in all stations. Target Hazard QuotientCd of mussels captured from Istanbul Strait was always determined <1, while it was equal to 1 for 50 kg individuals in Gelibolu samples. All THQAs were >1. Target carcinogenic Risk was evaluated for Pb and iAs, which were found to be negligible and acceptable, respectively. No biotoxins responsible for ASP, PSP, or DSP were detected. Hg levels were under detectable limits. Excluding Cd, the results did not reveal any risks associated with mussel consumption during mucilage.

Monitoring programme on toxic metal in bluefish (Pomatomus saltatrix), anchovy (Engraulis encrasicolus) and sardine (Sardina pilchardus) from Istanbul, Turkey: levels and estimated weekly intake.

Toxic metal (Hg, Cd, Pb, Cu and Zn) concentrations of small-medium bluefish, anchovy and sardine in Istanbul, Turkey, were determined using inductively coupled plasma-mass spectrometry (ICP-MS) throughout 1 year. The concentrations of pollutants were found to vary according to season and species. Estimates of weekly intake levels of the metals were calculated and compared to recommended safe limits for fish consumption by humans. The levels of Cd, Pb, Cu and Zn in the fillets of all species resulted in estimates of weekly intake levels that were lower than the recommended safe limits. The concentrations of Hg of small bluefish in September, of medium bluefish in June and September, of anchovy in March, and of sardine in August and September resulted in estimates of weekly intake levels that were higher than the recommended safe limits for human consumption.

Clinicopathological Factors Affecting Mucin 1, Mucin 2, and Mucin 5AC Staining in Patients who Underwent Resection for Colorectal Cancer.

OBJECTIVE: To investigate the clinicopathological factors affecting mucins (MUC 1, MUC 2, and MUC 5AC) staining in patients who underwent resection for colorectal cancer. STUDY DESIGN: An observational study. Place and Duration of the Study: Department of General Surgery and Department of Pathology, Kafkas University Faculty of Medicine, Kars, Turkey, between January 2020 and January 2021. METHODOLOGY: Patients operated on for colorectal adenocarcinoma were included in the study. Patients who underwent colorectal surgery for benign diseases or had a pathological diagnosis other than adenocarcinoma were excluded from the study. Clinicopathological factors affecting MUC1, MUC2, and MUC5AC staining were evaluated with appropriate statistical tests, assuming a significant p-value of less than 0.05. RESULTS: Of the 30 patients who met all study criteria, 18 (60%) were males. The mean age of all patients was 62.83±16.79 (21-88). MUC1 strongly positive staining was observed in 18 (60%) cases, and high expression was detected in pT4 and pT3 cases (p=0.005). In addition, increased expression was also noted in cases with lymph node involvement (p=0.045). MUC2 expression was more than 60% (strongly positive) in 20 (66.7%). The MUC2 expression was increased in moderately differentiated cases (p=0.032). There was no staining (negativity) in 22 (73.3%) cases with MUC5AC, and more than 60% staining (strongly positive) was observed in 3 (10%) cases. In addition, strong expression was noted in rectosigmoid tumours (p=0.001), female patients (p=0.046), and patients with pT3 and pT4 tumours (p=0.05). CONCLUSION: High MUC1 and high MUC5AC staining were observed in advanced colorectal cancer, whereas high MUC2 staining was observed in patients with moderate tumour differentiation. KEY WORDS: Colorectal cancers, Gene expressions, Mucin.

Assessment of health risks due to toxic metals in demersal fish captured from Saros and Edremit Bays, Northern Aegean Sea.

Bays are vulnerable ecosystems generally located near densely populated areas where toxic metals tend to accumulate and stay longer, affecting marine life. This study aimed to investigate the age-based health risks arising from Hg, Cd, Pb, and As in demersal fish captured from two major bays in the Aegean Sea. For this purpose, red mullet, whiting, piper gurnard, and tub gurnard, frequently consumed species, were caught from Saros and Edremit Bays. Toxic metal concentrations were determined from the muscle tissue of fish. Health risk assessments were conducted by the estimation of weekly intake (EWI), provisional tolerable weekly intake (PTWI), target hazard quotient (THQ), total THQ (TTHQ), and target carcinogenic risk (TR). Red mullet from Edremit Bay was the species with the highest toxic metal levels, which were 1.597 mg/kg, 0.041 mg/kg, 0.070 mg/kg, and 19.351 mg/kg for Hg, Cd, Pb, and As, respectively. Whiting from Edremit Bay had higher mean concentrations of Hg and As than those from Saros Bay. The levels of Hg, Pb, and As (0.328, 0.043, and 0.574 mg/kg) in the tub gurnard were higher in comparison with the piper gurnard (0.252, 0.020, and 0.382 mg/kg) caught in the same station in Saros. TTHQs of red mullet and whiting from the same bay were found to be > 1, indicating potential health risks for all nine age categories studied. On the other hand, TTHQs of all species from Saros Bay were determined to be > 1 for the first four age categories, which might trigger health risks for children and adolescents. According to the TR index for Pb, no risk was determined for the fish from both bays. However, TR calculations for inorganic As indicated high cancer risk in most of the age categories for red mullet and whiting from Edremit Bay. To sum up, the results revealed that the fish captured from Edremit Bay posed serious health risks in terms of Hg and As concentrations for all nine age categories. Surveillance and monitoring of toxic metal levels in demersal fish and population-based health risk evaluation are vital in heavily populated bays.

Blocking SIG1R Along with Low Cadmium Exposure Display Anti-cancer Qualities in Both MCF7 and MDA-MB-231 Cells.

Sigma-1 receptor (SIG1R) is a chaperone that modulates inositol 1,4,5-trisphosphate receptor type1 (IP3R1) calcium (Ca2+) channels on the endoplasmic reticulum. Therefore, SIG1R functions as an indirect regulator of Ca2+ and acts as an apoptosis modulator. Increased expression of SIG1R is associated with poor prognosis in breast cancers (BC), and SIG1R antagonists like BD1047 induce apoptosis. As a heavy metal, cadmium (Cd2+) is competitive with Ca2+ due to its physicochemical similarities and may trigger apoptosis at low concentrations. Our study investigated the SIG1R protein expression in 74 BC patients and found a significant increase in SIG1R expression in the triple-negative BC subtype. We also examined the apoptotic and anti-cancer effects of BD1047 in combination with CdCl2 in MCF7 and MDA-MB-213 cells. Cells were treated with CdCl2 at doses of 1 µM, 25 µM, and 50 µM, along with BD1047. Higher doses of CdCl2 were cytotoxic on both cancer cells and significantly increased DNA breaks. However, low-dose CdCl2 with BD1047 increased cell death and the apoptotic index in BC cells, although it did not exhibit cytotoxic effects on HUVEC cells. Co-administration of low-dose CdCl2 with BD1047 also reduced the migration and colony-forming ability of BC cells. Moreover, the expression of SIG1R protein in these groups decreased significantly compared to groups treated with BD1047 or low-dose CdCl2 alone. In conclusion, low-dose CdCl2 is thought to increase the apoptotic ability of BD1047 in BC cells by reducing SIG1R expression.

Sirt3, mitochondrial ROS, ageing, and carcinogenesis.

One fundamental observation in cancer etiology is that the rate of malignancies in any mammalian population increases exponentially as a function of age, suggesting a mechanistic link between the cellular processes governing longevity and carcinogenesis. In addition, it is well established that aberrations in mitochondrial metabolism, as measured by increased reactive oxygen species (ROS), are observed in both aging and cancer. In this regard, genes that impact upon longevity have recently been characterized in S. cerevisiae and C. elegans, and the human homologs include the Sirtuin family of protein deacetylases. Interestingly, three of the seven sirtuin proteins are localized into the mitochondria suggesting a connection between the mitochondrial sirtuins, the free radical theory of aging, and carcinogenesis. Based on these results it has been hypothesized that Sirt3 functions as a mitochondrial fidelity protein whose function governs both aging and carcinogenesis by modulating ROS metabolism. Sirt3 has also now been identified as a genomically expressed, mitochondrial localized tumor suppressor and this review will outline potential relationships between mitochondrial ROS/superoxide levels, aging, and cell phenotypes permissive for estrogen and progesterone receptor positive breast carcinogenesis.

Protective Effects of Betanin against Oxidative Stress in a Peripheral Artery Vasospasm Model in Rat.

Objective: The aim of this study is to determine protective/modulatory effects of betanin in a femoral artery vasospasm model in rats. Materials and Methods: Sprague-Dawley rats were divided into three groups. Group 1: sham (n = 7), group 2: vasospasm model only (n = 7), group 3: postoperative betanin treatment in the vasospasm model (n = 7). 100 mg/kg betanin was administered orally to group 3 for 7 days, postoperatively. Peripheral blood malondialdehyde (MDA) and nitric oxide (NO) levels were measured for the quantification of oxidative stress, lumen diameter and wall thickness of femoral artery segments were determined to assess vasodilator effects of betanin. Results: Femoral artery vasospasm formation significantly increased both MDA (13.54 ± 3.09 mmol/mL) and NO levels (0.61 ± 0.06 µmol/mL) relative to the sham (9.07 ± 1.09 and 0.48 ± 0.1, respectively). Upon betanin administration, both MDA and NO approached baseline levels (9.95 ± 0.92 and 0.5 ± 0.06, respectively). Pathological examination of lumen diameter and wall thickness of the femoral arteries also revealed that betanin administration resulted in significant increase in lumen diameter when compared to vasospasm group (614.15 ± 245.77 versus 117.40 ± 46.19 µm) and decrease in wall thickness (64.68 ± 14.13 versus 96.73 ± 9.20 µm). Conclusion: Betanin was shown to have protective effect against oxidative stress in a peripheral artery vasospasm model in rats. It may also have a role in mitigating maladaptive changes in arterial structure, as shown in pathological examination.

The protective effect of betanin and copper on spinal cord ischemia-reperfusion injury.

Context: Both copper and betanin have been implicated as having significant bioactivity against ischemic damage in a variety of experimental and clinical settings. The aim of this study is to investigate whether betanin and copper have any protective effect on spinal cord in an ischemia-reperfusion (I/R) model in rats.Design: Spraque-Dawley rats were used in four groups: Sham group (n = 7), control group (laparotomy and cross-clamping of aorta, n = 7), betanin treatment group (dosage of 100 mg/kg of betanin administered intraperitoneally (i.p.) 60 min before laparotomy, n = 7), copper sulfate treatment group (administered copper sulfate i.p. at a dose of 0.1 mg/kg/day for 7 days before laparotomy, n = 7). Malondialdehyde (MDA), glutathione (GSH) levels, myeloperoxidase (MPO) and superoxide dismutase (SOD) activity were measured. Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay was also performed to evaluate apoptosis.Setting: Kafkas University, Faculty of Medicine, Kars, Turkey.Results: I/R injury was successfully demonstrated with the surgical model. Betanin and copper treatment significantly decreased MDA levels, MPO activity and the number of apoptotic cells in the spinal cord. Betanin and copper treatment significantly increased GSH levels. Copper treatment significantly increased SOD activity, whereas betanin was not as effective. Apoptotic cells were significantly decreased in both treatment groups.Conclusion: I/R injury of the spinal cord can be successfully demonstrated by aortic clamping in this surgical model. Betanin/Copper sulphate has ameliorative effects against operative I/R injury. Low toxicity of those agents makes them ideal targets for clinical research for this purpose.

Seasonal differences in the trace metal and macrominerals in shrimp (Parapenaus longirostris) from Marmara Sea.

Seasonal changes in micromineral and macromineral concentrations in tissues of shrimp (Parapenaus longirostris) from Marmara Sea were measured for a 1-year period by using inductively coupled plasma mass spectrometer. The contents of investigated minerals in shrimp were found to be in the range of 0.374-0.716 mg/kg for Hg, 0.526-1.286 mg/kg for Se, 0.007-0.098 mg/kg for Cd, 0.197-0.230 mg/kg for Pb, 5.194-7.600 mg/kg for Cu, 11.090-17.707 mg/kg for Zn, 22.128-38.850 mg/kg for Al, 61.769-88.437 mg/kg for Fe, 0.262-0.368 mg/kg for As, 0.081-0.249 mg/kg for Co, 0.850-1.459 mg/kg for Mn, 0.316-0.507 mg/kg for Ni, 0.032-0.107 mg/kg for Sn, 1.262-1.502 mg/kg for Cr, 2,813.770-3,317.819 mg/kg for Na, 3,702.230-4,479.648 mg/kg for K, 495.782-650.280 mg/kg for Mg, 790.407-1,016.112 mg/kg for Ca, 2,685.873-3,657.658 mg/kg for P, and 0.454-0.942 mg/kg for I. The levels of Hg found in autumn were higher than maximum levels proposed by the European legislation.

Determination of mineral composition in three commercial fish species (Solea solea, Mullus surmuletus, and Merlangius merlangus).

This study was monitored to determine the changes in the micromineral and macromineral composition of common sole (Solea solea), striped red mullet (Mullus surmuletus), and whiting (Merlangius merlangus) throughout the year. Macromineral concentrations in edible parts of fish species were 444-1,559 mg/kg for Na, 1,975-5,130 mg/kg for K, 228-658 mg/kg for Mg, 187-1,105 mg/kg for Ca, and 2,341-7,341 for P, respectively. The highest mercury contents were found in the autumn months. While the highest protein and lowest fat values were found in the summer, the highest ash contents were found in the spring. Mercury content was found to be over the legislative limits in autumn samples for common sole and in summer for striped red mullet. Lead and cadmium contents of striped red mullet were found to be over the legislative limits throughout year.

Seasonal variations in the macronutrient mineral and proximate composition of two clams (Chamelea gallina and Donax trunculus).

Two bivalve's species (Chamelea gallina and Donax trunculus) were investigated in terms of proximate and mineral compositions (sodium, potassium, magnesium, calcium, iodine and selenium) throughout the year. The concentrations of minerals were determined using inductively coupled plasma mass spectrometry. Ranges of moisture, protein, fat, ash and carbohydrate contents were 82.70-86.57%, 6.86-8.99%, 0.58-1.20%, 2.44-2.95% and 2.70-4.50% for C. gallina, and were 81.09-85.55%, 8.13-10.61%, 0.69-1.33%, 3.19-4.06% and 2.31-3.18% for D. trunculus, respectively. The highest sodium, potassium, magnesium, calcium, iodine and selenium contents for two species were found in the summer, followed by spring, autumn and winter. The concentrations of metals in two tissues exceeded the acceptable levels for a food source for human consumption.

Expression profile and cellular localizations of mucin proteins, CK7, and cytoplasmic p27 in Barrett's esophagus and esophageal adenocarcinoma.

PURPOSE: Barrett's esophagus is one of the main risk factors for increased incidence of esophageal adenocarcinoma. In this study, we studied protein expression levels and cellular localizations of MUC-1, MUC-2, MUC-5AC, CK7, and cytoplasmic p27 to assess the relationship between the expression of each of these proteins and the disease progression on endoscopic biopsies. MATERIALS AND METHODS: Immunohistochemical analyses were performed using antibodies produced against MUC-1, MUC-2, MUC-5AC, CK7, and p27. Endoscopic specimens of esophageal mucosa were obtained from 72 patients who underwent esophagectomy for Barrett's esophagus, metaplasia, dysplasia, or esophageal adenocarcinoma developed from Barrett's esophagus. RESULTS: Multilayer squamous epithelium showed only MUC-1 positivity in the EAC group while MUC-2 and MUC-5AC staining could not be detected in this group. Strong and diffused membranous or cytoplasmic staining of CK7 was observed at squamous, ductal, surface columnar and/or glandular epithelium. c-p27 staining was diffused and moderate in the cellular membranes observed in all groups except for esophageal epithelial metaplasia without intestinal metaplasia. Additionally, weakly focal cytoplasmic staining in squamous epithelium of p27 in EAC was detected. CONCLUSIONS: Barrett's esophagus, which has a heterogeneous epithelium, might yield different diagnosis based on endoscopic evaluation and immunohistological investigation. Thus, the use of MUC1, p27, and CK7 might strengthen the truthful diagnosis. MUC-1, CK7, and c-p27 immunostaining can be used as the predictive markers for esophageal cancer progression from Barrett's esophagus.

Inhibition of Sirtuin 6 Induces Neuroblastoma Differentiation.

BACKGROUND/AIM: Sirtuins (SIRTs) play crucial roles in various signaling pathways that modulate differentiation and proliferation. We sought to elucidate the role of SIRTs in differentiation and proliferation of human neuroblastoma (NB). MATERIALS AND METHODS: NB cells were treated with nicotinamide (NAM), a non-specific SIRT inhibitor, SIRT-targeted short hairpin RNAs, and retinoic acid to assess cell growth and differentiation. RESULTS: SIRTs are involved in proliferation and differentiation using NAM in BE(2)-C cells. Specifically, SIRT6 knockdown in BE(2)-C cells reduced cell proliferation, induced neurite extension, corresponding with induction of p21CIP1 expression and G1 cell-cycle arrest. These effects were rescued by forced re-overexpression of SIRT6. SIRT6 expression was reduced in differentiated human NB sections, and RA-induced differentiation in BE(2)-C cells. CONCLUSION: SIRTs have important oncogenic properties in NB beyond its established functions in aging and genome stability. SIRT6 may represent a novel target for developing future therapeutics for the treatment of aggressive NBs.

NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway.

Colorectal cancer (CRC) remains a common and deadly cancer due to metastatic disease. Activin and TGFB (TGFß) signaling are growth suppressive pathways that exert non-canonical pro-metastatic effects late in CRC carcinogenesis. We have recently shown that activin downregulates p21 via ubiquitination and degradation associated with enhanced cellular migration independent of SMADs. To investigate the mechanism of metastatic activin signaling, we examined activated NFkB signaling and activin ligand expression in CRC patient samples and found a strong correlation. We hypothesize that activation of the E3 ubiquitin ligase MDM2 by NFkB leads to p21 degradation in response to activin treatment. To dissect the link between activin and pro-carcinogenic NFkB signaling and downstream targets, we found that activin but not TGFB induced activation of NFkB leading to increased MDM2 ubiquitin ligase via PI3K. Further, overexpression of wild type p65 NFkB increased MDM2 expression while the NFkB inhibitors NEMO-binding domain (NBD) and Bay11-7082 blocked the activin-induced increase in MDM2. In conclusion, in colon cancer cell migration, activin utilizes NFkB to induce MDM2 activity leading to the degradation of p21 in a PI3K dependent mechanism. This provides new mechanistic knowledge linking activin and NFkB signaling in advanced colon cancer which is applicable to targeted therapeutic interventions.

Activin signaling is an essential component of the TGF-ß induced pro-metastatic phenotype in colorectal cancer.

Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-ß superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-ß superfamily members activin and TGF-ß in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue activin and TGF-ß ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-ß growth suppression is independent of activin, TGF-ß treatment leads to increased activin secretion in colon cancer cells and TGF-ß induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-ß pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-ß pathway members. In conclusion, activin and TGF-ß are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF-ß signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions.