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  • Cellular signal transduction and cancer metastasis
Metastatic disease is largely incurable because of its systemic nature and the resistance of disseminated tumor cells to existing therapeutic agents. To colonize distant organs, circulating tumor cells must overcome many obstacles, including surviving in circulation, infiltrating distant tissues, evading immune defenses, adapting to supportive niches, surviving as latent tumor-initiating seeds and eventually breaking out to replace the host tissue. Metastasis is a highly inefficient process and the mechanisms are poorly understood. Mutiple cellular signaling are involved in all these metastatic processes. We are searching for mechanisms of metastasis and the therapeutic methods of preventing it from occurence. 

  • Exosome in human diseases 
Exosome are cell-derived vesicles that are present in many and perhaps all eukaryotic fluids, including blood, urine, and cultured medium of cell cultures. The reported diameter of exosomes is between 50 and 150 nm. Exosomes are either released from the cell whenmutivesicular bodies fuse with the plasma membrane or released directly from the plasma membrane. Evidence is accumulating that exosomes have specialized functions and play a key role in processes such as coagulation, intercellular signaling, and waste management. Cancer exosome secreated from tumor initiating cell, circulating tuomr cells, mediate cancer progression. Thus exosomes can potentially be used for prognosis, for therapy, and as biomarkers for health and disease. We are working on exosome and looking for new technology, new understanding and new application of exosome.  

2012 highlight: USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor.
The stability and membrane localization of the transforming growth factor-β (TGF-β) type I receptor (TβRI) determines the levels of TGF-β signalling. TβRI is targeted for ubiquitylation-mediated degradation by the SMAD7-SMURF2 complex. We performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-β signalling. USP4 was found to directly interact with TβRI and act as a deubiquitylating enzyme, thereby controlling TβRI levels at the plasma membrane. Depletion of USP4 mitigates TGF-β-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and TβRI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-β and AKT signalling pathways.

2013 highlight: TRAF4 Promotes TGF-β Receptor Signaling and Drives Breast Cancer Metastasis
TGF-β signaling is a therapeutic target in advanced cancers. We identified tumor necrosis factor receptor-associated factor 4 (TRAF4) as a key component mediating pro-oncogenic TGF-β-induced SMAD and non-SMAD signaling. Upon TGF-β stimulation, TRAF4 is recruited to the active TGF-β receptor complex, where it antagonizes E3 ligase SMURF2 and facilitates the recruitment of deubiquitinase USP15 to the TGF-β type I receptor (TβRI). Both processes contribute to TβRI stabilization on the plasma membrane and thereby enhance TGF-β signaling. In addition, the TGF-β receptor-TRAF4 interaction triggers Lys 63-linked TRAF4 polyubiquitylation and subsequent activation of the TGF-β-activated kinase (TAK)1. TRAF4 is required for efficient TGF-β-induced migration, epithelial-to-mesenchymal transition, and breast cancer metastasis. Elevated TRAF4 expression correlated with increased levels of phosphorylated SMAD2 and phosphorylated TAK1 as well as poor prognosis among breast cancer patients. Our results demonstrate that TRAF4 can regulate the TGF-β pathway and is a key determinant in breast cancer pathogenesis.

2014 highlight: Nuclear receptor NR4A1 promotes breast cancer invasion and metastasis by activating TGF-β signalling
In advanced cancers, the TGF-β pathway acts as an oncogenic factor and is considered to be a therapeutic target. Here using a genome-wide cDNA screen, we identify nuclear receptor NR4A1 as a strong activator of TGF-β signalling. NR4A1 promotes TGF-β/SMAD signalling by facilitating AXIN2–RNF12/ARKADIA-induced SMAD7 degradation. NR4A1 interacts with SMAD7 and AXIN2, and potently and directly induces AXIN2 expression. Whereas loss of NR4A1 inhibits TGF-β-induced epithelial-to-mesenchymal transition and metastasis, slight NR4A1 ectopic expression stimulates metastasis in a TGF-β-dependent manner. Importantly, inflammatory cytokines potently induce NR4A1 expression, and potentiate TGF-β-mediated breast cancer cell migration, invasion and metastasis in vitro and in vivo. Notably, NR4A1 expression is elevated in breast cancer patients with high immune infiltration and its expression weakly correlates with phosphorylated SMAD2 levels, and is an indicator of poor prognosis. Our results uncover inflammation-induced NR4A1 as an important determinant for hyperactivation of pro-oncogenic TGF-β signalling in breast cancer.

2015 highlight: c-Myb drives Wnt dependent metastasis
The molecular underpinnings of aggressive breast cancers remain mainly obscure. Here we demonstrate that activation of the transcription factor c-Myb is required for the pro-metastatic character of basal breast cancers. An analysis of breast cancer patients led us to identify c-Myb as an activator of Wnt/β-catenin signaling. c-Myb interacted with the intracellular Wnt effector β-catenin and co-activated the Wnt/β-catenin target genes Cyclin D1 and Axin2. Moreover, c-Myb controlled metastasis in an Axin2 dependent manner. Expression microarray analyses revealed a positive association between Axin2 and c-Myb, a target of the pro-inflammatory cytokine IL-1β that was found to be required for IL-1β-induced breast cancer cell invasion. Overall, our results identified c-Myb as a promoter of breast cancer invasion and metastasis through its ability to activate Wnt/β-catenin/Axin2 signaling. 

2016 highlight: Loss of FAF1 accumulates TβRII for metastasis
We found FAF1 destabilizes TβRII on the cell surface by recruiting VCP/E3 ligase complex thereby limiting excessive TGF-β response. The activated AKT directly phosphorylates FAF1 at Ser 582 then disrupts the FAF1-VCP complex and reduces FAF1 at the plasma membrane. The latter results in an increase in TβRII at the cell surface that promotes both TGF-β-induced SMAD and non-SMAD signaling. We uncover metastasis suppressing role for FAF1 through analyses of FAF1-knockout animals, various in vitro and in vivo models of epithelial to mesenchymal transition and metastasis, an MMTV-PyMT transgenic model of mammary tumor progression and clinical breast cancer samples. These findings uncover a previously uncharacterized mechanism by which TβRII is tightly controlled. Importantly, we reveal how SMAD and AKT pathways interact to confer pro-oncogenic responses to TGF-β.

2017 highlight: On going!
 
 
Cell signaling pathways
We also explored widely the other cellular signaling that are involved in human cancer metastasis, such as Wnt, BMP, NFκB, PI3K/AKT, Hippo, p53 and innate immune pathways.
 
Focusing on human deubiquitinating enzymes (DUBs)
Deubiquitinating enzymes, which mediate the removal and processing of ubiquitin, are functionally important but less well understood. We systematically study DUBs in tumor oncogenesis with focus on their function, specificity, and the regulation of their activity.
                      
 (human DUB family members. Cell. 2005 Dec)