Mutations of the BRCA1 tumor suppressor gene are the most commonly detected alterations in familial breast and ovarian cancer. Although BRCA1 is required for normal mouse development, the molecular basis for its tumor suppressive function remains poorly understood. We show here that BRCA1 increases p53-dependent transcription from the p21 WAF1/CIP1 and bax promoters. We also show that BRCA1 and p53 proteins interact both in vitro and in vivo. The interacting regions map, in vitro, to aa 224 ± 500 of BRCA1 and the C-terminal domain of p53. Tumor-derived transactivation-de®cient BRCA1 mutants are defective in co-activation of p53-dependent transcription and a truncation mutant of BRCA1 that retains the p53-interacting region acts as a dominant inhibitor of p53-dependent transcription. BRCA1 and p53 cooperatively induce apoptosis of cancer cells. The results indicate that BRCA1 and p53 may coordinately regulate gene expression in their role as tumor suppressors.

ObjectiveWe compared the increases in the prevalence of gestational diabetes mellitus (GDM) based on the 1999 World Health Organization (WHO) criteria and its risk factors in Tianjin, China, over a 12-year period. We also examined the changes in the prevalence using the criteria of International Association of Diabetes and Pregnancy Study Group (IADPSG).MethodsIn 2010-2012, 18589 women who registered within 12 weeks of gestation underwent a glucose challenge test (GCT) at 24-28 gestational weeks. Amongst them, 2953 women with 1-hour plasma glucose ≥7.8 mmol/L underwent a 75-gram 2-hour oral glucose tolerance test (OGTT) and 781 women had a positive GCT but absented from the standard OGTT. An adjusted prevalence of GDM was calculated for the whole cohort of women by including an estimate of the proportion of women with positive GCTs who did not have OGTTs but would have been expected to have GDM. Logistic regression was used to obtain odds ratios and 95% confidence intervals using the IADPSG criteria. The prevalence of GDM risk factors was compared to the 1999 survey.ResultsThe adjusted prevalence of GDM by the 1999 WHO criteria was 8.1%, a 3.5-fold increase as in 1999. Using the IADPSG criteria increased the adjusted prevalence further to 9.3%. Advanced age, higher pre-pregnancy body mass index, Han-nationality, higher systolic blood pressure (BP), a family history of diabetes, weight gain during pregnancy and habitual smoking were risk factors for GDM. Compared to the 1999 survey, the prevalence of overweight plus obesity had increased by 1.8 folds, age≥30 years by 2.3 folds, systolic BP by 2.3 mmHg over the 12-year period.ConclusionsIncreasing prevalence of overweight/obesity and older age at pregnancy were accompanied by increasing prevalence of GDM, further increased by change in diagnostic criteria.

BackgroundOxaliplatin resistance is a major challenge for treatment of advanced colorectal cancer (CRC). Both acquisition of epithelial-mesenchymal transition (EMT) and suppressed drug accumulation in cancer cells contributes to development of oxaliplatin resistance. Aberrant expression of small noncoding RNA, miR-128-3p, has been shown to be a key regulator in tumorigenesis and cancer development. However, its roles in the progression of CRC and oxaliplatin-resistance are largely unknown.MethodsOxaliplatin-resistant CRC and normal intestinal FHC cells were transfected with a miR-128-3p expression lentivirus. After transfection, FHC-derived exosomes were isolated and co-cultured with CRC cells. miR-128-3p expression in resistant CRC cells, FHC cells, and exosomes was quantified by quantitative real-time PCR (RT-qPCR). The mRNA and protein levels of miR-128-3p target genes in resistant CRC cells were quantified by RT-qPCR and western blot, respectively. The effects of miR-128-3p on CRC cell viability, apoptosis, EMT, motility and drug efflux were evaluated by CCK8, flow cytometry, Transwell and wound healing assays, immunofluorescence, and atomic absorption spectrophotometry. Xenograft models were used to determine whether miR-128-3p loaded exosomes can re-sensitize CRC cells to oxaliplatin in vivo.ResultsIn our established stable oxaliplatin-resistant CRC cell lines, in vitro and vivo studies revealed miR-128-3p suppressed EMT and increased intracellular oxaliplatin accumulation. Importantly, our results indicated that lower miR-128-3p expression was associated with poor oxaliplatin response in advanced human CRC patients. Moreover, data showed that miR-128-3p-transfected FHC cells effectively packaged miR-128-3p into secreted exosomes and mediated miR-128-3p delivery to oxaliplatin-resistant cells, improving oxaliplatin response in CRC cells both in vitro and in vivo. In addition, miR-128-3p overexpression up-regulated E-cadherin levels and inhibited oxaliplatin-induced EMT by suppressing Bmi1 expression in resistant cells. Meanwhile, it also decreased oxaliplatin efflux through suppressed expression of the drug transporter MRP5.ConclusionOur results demonstrate that miR-128-3p delivery via exosomes represents a novel strategy enhancing chemosensitivity in CRC through negative regulation of Bmi1 and MRP5. Moreover, miR-128-3p may be a promising diagnostic and prognostic marker for oxaliplatin-based chemotherapy.Electronic supplementary materialThe online version of this article (10.1186/s12943-019-0981-7) contains supplementary material, which is available to authorized users.