Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain- and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed chemoresistance. Moreover, co-administration of the inhibitors of MUC1–EGFR–ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.
It is generally recognized that the AIDS epidemic will have a negative effect on the orphans' school education. However, few studies have been carried out to examine the school performance and school behavior of AIDS orphans and vulnerable children (children living with HIV-infected parents). Using both self-report and teacher evaluation data of 1625 children from rural central China, we examined the impact of parental HIV/AIDS on children's school performances (academic marks, educational expectation, and student leadership) and school behaviors (e.g., aggression, shy/anxious and assertive social skills). Results indicate that AIDS orphans and vulnerable children had disadvantages in school performances in comparison to their peers from the same community who did not experience AIDSrelated death and illness in their family (comparison children). AIDS orphans had the lowest academic marks based on the reports of both children and teachers. Educational expectation was significantly lower among AIDS orphans and vulnerable children than comparison children from teacher's perspective. AIDS orphans were significantly more likely to demonstrate aggressive, impulsive and anxious behaviors than non-orphans. Moreover, orphans have more learning difficulties. Vulnerable children were also at a disadvantage on most measures. The data suggest that a greater attention is needed to the school performance and behavior of children affected by AIDS. The findings also indicate that AIDS relief and assistance program for children should go beyond the school attendance and make efforts to improve their school performance and education aspiration.
The resistance to azoles may be associated with the mutations in ERG11 but not ERG4 gene in C. albicans isolates. In addition, overexpressed ERG4 and ERG11 genes are found in resistant C. albicans isolates, and the mRNA levels of ERG4 may be irrelevant to ERG11 in resistant C. albicans isolates.
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