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Rationale: Mxi1 is regarded as a potential tumor suppressor protein that antagonizes the transcriptional activity of proto-oncogene Myc. However, the clinical significances and underlying mechanisms by which Mxi1 is regulated in lung cancer remain poorly understood.Methods: Mass spectrometry analysis and immunoprecipitation assay were utilized to detect the protein-protein interaction. The phosphorylation of Mxi1 was evaluated by in vitro kinase assays. Poly-ubiquitination of Mxi1 was examined by in vivo ubiquitination assay. Lung cancer cells stably expressing wild-type Mxi1 or Mxi1-S160A were used for functional analyses. The expression levels of Mxi1 and S6K1 were determined by immunohistochemistry in lung cancer tissues and adjacent normal lung tissues.Results: We found that Mxi1 is downregulated and correlated with poor prognosis in lung cancer. Using tandem affinity purification technology, we provided evidence that β-Trcp E3 ubiquitin ligase interacts with and promotes the ubiquitination and degradation of Mxi1. Furthermore, we demonstrated that Mxi1 is phosphorylated at S160 site by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase β-Trcp. Moreover, a phosphorylation mutant form of Mxi1 (Mxi1-S160A), which cannot be degraded by S6K1 and β-Trcp, is much more stable and efficient in suppressing the transcriptional activity of Myc and radioresistance in lung cancer cells. More importantly, a strong inverse correlation between S6K1 and Mxi1 expression was observed in human lung cancer tissues.Conclusion: Our findings not only establish a crosstalk between the mTOR/S6K1 signaling pathway and Myc activation, but also suggest that targeting S6K1/Mxi1 pathway is a promising therapeutic strategy for the treatment of lung cancer.

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UBE2O, an E2/E3 hybrid ubiquitin-protein ligase, has been implicated in the regulation of adipogenesis, erythroid differentiation, and tumor proliferation. However, its role in cancer radioresistance remains completely unknown. Here, we uncover that UBE2O interacts and targets Mxi1 for ubiquitination and degradation at the K46 residue. Furthermore, we show that genetical or pharmacological blockade of UBE2O impairs tumor progression and radioresistance in lung cancer in vitro and in vivo, and these effects can be restored by Mxi1 inhibition. Moreover, we demonstrate that UBE2O is overexpressed and negatively correlated with Mxi1 protein levels in lung cancer tissues. Collectively, our work reveals that UBE2O facilitates tumorigenesis and radioresistance by promoting Mxi1 ubiquitination and degradation, suggesting that UBE2O is an attractive radiosensitization target for the treatment of lung cancer.

In this paper, an effective existence theorem for periodic Markov process is first established. Using the theorem, we consider a class of periodic Itô stochastic functional differential equations, and some sufficient conditions for the existence of periodic solution of the equations are given. To overcome the difficulties created by the special features possessed by the periodic stochastic differential equations with delays, as one will see, several lemmas are introduced. These existence theorems are rather general and therefore have great power in applications. Especially, our results are natural generalization of some classical periodic theorems on the model without stochastic perturbation. An example is worked out to demonstrate the advantages of our results.

The main aim of this paper is to develop some basic theories of stochastic functional differential equations (SFDEs). Firstly, we establish stochastic versions of the well-known Picard local existence-uniqueness theorem given by Driver and continuation theorems given by Hale and Driver for functional differential equations (FDEs). Then, we extend the global existence-uniqueness theorems of Wintner for ordinary differential equations (ODEs), Driver for FDEs and Taniguchi for stochastic ordinary differential equations (SODEs) to SFDEs. These show clearly the power of our new results.