MicroRNAs have key roles in tumor metastasis. Here, we describe the regulation and function of miR-34a and miR-34c (miR-34a/c) in breast cancer metastasis. Expression analysis verified that miR-34a/c expression is significantly decreased in metastatic breast cancer cells and human primary breast tumors with lymph node metastases. Overexpression of miR-34a/c could inhibit breast cancer cell migration and invasion in vitro and distal pulmonary metastasis in vivo. Further studies revealed that Fos-related antigen 1 (Fra-1 or Fosl1) is a downstream target of miR-34a/c as miR-34a/c bound directly to the 3'untranslated region of Fra-1, subsequently reducing both the mRNA and protein levels of Fra-1. Silencing of Fra-1 recapitulated the effects of miR-34a/c overexpression, whereas enforced expression of Fra-1 reverses the suppressive effects of miR-34a/c. Moreover, significant downregulation of miR-34a in metastatic breast cancer tissues was found to be inversely correlated with Fra-1 expression. Our results demonstrate that miR-34a/c functions as a metastasis suppressor to regulate breast cancer migration and invasion through targeting Fra-1 oncogene and suggest a therapeutic application of miR-34 in breast cancer.

As one of the most common intracranial tumors, pituitary tumor is associated with high morbidity. Effective therapy is currently not available for some pituitary tumors due to the largely undefined pathological processes of pituitary tumorigenesis. In this study, hyperactivation of mammalian/mechanistic target of rapamycin (mTOR) signaling was observed in estrogen-induced rat pituitary tumor and mTOR inhibitor rapamycin blocked the tumor development. Pituitary knockout of either mTOR signaling pathway negative regulator Tsc1 or Pten caused mouse pituitary prolactinoma, which was abolished by rapamycin treatment. Mechanistically, the expression of pituitary tumor transforming gene 1 (PTTG1) was upregulated in an mTOR complex 1-dependent manner. Overexpressed PTTG1 was crucial in hyperactive mTOR-mediated tumorigenesis. mTOR-PTTG1 signaling axis may be targeted for the treatment of tumors with mTOR hyperactivation.

PIM1 is a proto-oncogene, encoding a serine/threonine protein kinase that regulates cell proliferation, survival, differentiation and apoptosis. Previous reports suggest that overexpression of PIM1 can induce cellular senescence. However, the molecular mechanism underlying this process is not fully understood. Here we report that UHRF1 is a novel substrate of PIM1 kinase, which could be phosphorylated at Ser311 and therefore promoted to degradation. Our data demonstrates that PIM1 destabilizes UHRF1, leading to DNA hypomethylation, which consequently results in genomic instability, increased p16 expression and subsequent induction of cellular senescence. Taken together, our results suggest that down-regulation of UHRF1 is an important mechanism of PIM1-mediated cellular senescence.

BackgroundDespite decades of study, debates exist surrounding the relationship between education and functional health status transition among elderly populations. This study aims to add evidence to the debates using China as a case study. Specifically, this study analysed the association of education with functional health status transition and then the mechanism behind that association using the budget constraint relax hypothesis and the efficiency improvement hypothesis among elderly population in China.MethodsBased on data from the Chinese Longitudinal Healthy Longevity Surveys from 2008 and 2011, this study focussed on adults aged 65 years and above, with a final sample size of 12,112. A generalised structural equation model was used to analyse the relationship between education and functional health status transition and the mechanism behind that association.ResultsDuring the three examined years, among elderly adults who were nondisabled at baseline, 53.1% stayed nondisabled, 14.6% became disabled, and 32.3% died; among those disabled in 2008, 8.1% recovered, 21.6% stayed disabled, and 70.3% died. Compared with older adults without any education, those who had attended primary schools had both lower mortality and disability, whereas those who had attended high schools and above only had a lower mortality rate. The budget constraint relax hypothesis and the efficiency improvement hypothesis explained the majority of the relationship between education and transition from non-disability to death, but hardly explained the transition from non-disability to disability. Furthermore, once a person was disabled, education had no significant relationship with functional ability recovery or mortality.ConclusionsAttending primary school seems to provide the highest benefit to functional health status transition among older and nondisabled persons in China. Those who attended high schools and above are expected to live a longer life with disability. The mechanism between education and the onset of disability needs more discussion.

The first sentence of the Materials and Methods section should read as follows. "The test isolates, which were collected from September to December 2006, were drawn from the Chinese Meropenem Susceptibility Surveillance study collection, which consists of nonrepeat clinical isolates of specified enterobacterial genera annually collected by specified laboratories in each of the big nine cities in China." 847