Three-Dimensional Nuclear Telomere Profiling as a Biomarker for Recurrence in Oligodendrogliomas: A Pilot Study.

Mechanisms of recurrence in oligodendrogliomas are poorly understood. Recurrence might be driven by telomere dysfunction-mediated genomic instability. In a pilot study, we investigated ten patients with oligodendrogliomas at the time of diagnosis (first surgery) and after recurrence (second surgery) using three-dimensional nuclear telomere analysis performed with quantitative software TeloView® (Telo Genomics Corp, Toronto, Ontario, Canada). 1p/19q deletion status of each patient was determined by fluorescent in situ hybridization on touch preparation slides. We found that a very specific 3D telomeric profile was associated with two pathways of recurrence in oligodendrogliomas independent of their 1p/19q status: a first group of 8 patients displayed significantly different 3D telomere profiles between both surgeries (p < 0.0001). Their recurrence happened at a mean of 231.375 ± 117.42 days and a median time to progression (TTP) of 239 days, a period defined as short-term recurrence; and a second group of three patients displayed identical 3D telomere profiles between both surgery samples (p > 0.05). Their recurrence happened at a mean of 960.666 ± 86.19 days and a median TTP of 930 days, a period defined as long-term recurrence. Our results suggest a potential link between nuclear telomere architecture and telomere dysfunction with time to recurrence in oligodendrogliomas, independently of the 1p/19q status.

Monitoring of autophagy is complicated--salinomycin as an example.

Monitoring of autophagy is challenging because of its multiple steps and lack of single befitting technique for a complete mechanistic understanding, which makes the task complicated. Here, we evaluate the functionality of autophagy triggered by salinomycin (anti-cancer stem cell agent) using flow cytometry and advanced microscopy. We show that salinomycin does induce functional autophagy at lower concentrations and such a dose is cell type-dependent. For example, PC3 cells show active autophagic flux at 10 µM concentration of salinomycin while murine embryonic fibroblasts already show an inhibition of flux at such doses. A higher concentration of salinomycin (i.e. 30 µM) inhibits autophagic flux in both cell types. The data confirms our previous findings that salinomycin is an inducer of autophagy, whereas autophagic flux inhibition is a secondary response.

Salinomycin induces activation of autophagy, mitophagy and affects mitochondrial polarity: differences between primary and cancer cells.

The molecular mechanism of Salinomycin's toxicity is not fully understood. Various studies reported that Ca(2+), cytochrome c, and caspase activation play a role in Salinomycin-induced cytotoxicity. Furthermore, Salinomycin may target Wnt/ß-catenin signaling pathway to promote differentiation and thus elimination of cancer stem cells. In this study, we show a massive autophagic response to Salinomycin (substantially stronger than to commonly used autophagic inducer Rapamycin) in prostrate-, breast cancer cells, and to lesser degree in human normal dermal fibroblasts. Interestingly, autophagy induced by Salinomycin is a cell protective mechanism in all tested cancer cell lines. Furthermore, Salinomycin induces mitophagy, mitoptosis and increased mitochondrial membrane potential (∆Ψ) in a subpopulation of cells. Salinomycin strongly, and in time-dependent manner decreases cellular ATP level. Contrastingly, human normal dermal fibroblasts treated with Salinomycin show some initial decrease in mitochondrial mass, however they are largely resistant to Salinomycin-triggered ATP-depletion. Our data provide new insight into the molecular mechanism of preferential toxicity of Salinomycin towards cancer cells, and suggest possible clinical application of Salinomycin in combination with autophagy inhibitors (i.e. clinically-used Chloroquine). Furthermore, we discuss preferential Salinomycins toxicity in the context of Warburg effect.

Association of MicroRNA-652 Expression with Radiation Response of Colorectal Cancer: A Study from Rectal Cancer Patients in a Swedish Trial of Preoperative Radiotherapy.

BACKGROUND: Radiotherapy is a standard adjuvant therapy in patients with progressive rectal cancer, but many patients are resistant to radiotherapy, leading to poor prognosis. Our study identified microRNA-652 (miR-652) value on radiotherapy response and outcome in rectal cancer patients. METHODS: miR-652 expression was determined by qPCR in primary rectal cancer from 48 patients with and 53 patients without radiotherapy. The association of miR-652 with biological factors and the prognosis was examined. The biological function of miR-652 was identified through TCGA and GEPIA database searches. Two human colon cancer cell lines (HCT116 p53+/+ and p53-/-) were used for in vitro study. The molecular interactions of miR-652 and tumor suppressor genes were studied through a computational approach. RESULTS: In RT patients, miR-652 expression was significantly decreased in cancers when compared to non-radiotherapy cases (P = 0.002). High miR-652 expression in non-RT patients was with increased apoptosis marker (P = 0.036), ATM (P = 0.010), and DNp73 expression (P = 0.009). High miR-652 expression was related to worse disease-free survival of non-radiotherapy patients, independent of gender, age, tumor stage, and differentiation (P = 0.028; HR = 7.398, 95% CI 0.217-3.786). The biological functional analysis further identified the prognostic value and potential relationship of miR-652 with apoptosis in rectal cancer. miR-652 expression in cancers was negatively related to WRAP53 expression (P = 0.022). After miR-652 inhibition, the estimation of reactive oxygen species, caspase activity, and apoptosis in HCT116 p53+/+ cells was significantly increased compared with HCT116 p53-/- cells after radiation. The results of the molecular docking analysis show that the miR652-CTNNBL1 and miR652-TP53 were highly stable. CONCLUSION: Our findings suggest the potential value of miR-652 expression as a marker for the prediction of radiation response and clinical outcome in rectal cancer patients.