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Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation. Knock down of GP78 significantly increased the expression of HSPA5 and enhanced migration/invasive ability of breast cancer cells. Knock down of histone deacetylase-6 (HDAC6) increased the acetylation of HSPA5 at lysine residues 353 (K353) and reduced GP78-mediated ubiquitination of HSPA5 at K447 and then increased cell migration/invasion. In addition, we demonstrate that E3 ubiquitin ligase GP78 preferentially binds to deacetylated HSPA5. Notably, the expression levels of GP78 inversely correlated with HSPA5 levels in breast cancer patients. Patients with low GP78 expression significantly correlated with invasiveness of breast cancer, advanced tumor stages and poor clinical outcome. Taken together, our results provide new mechanistic insights into the understanding that deacetylation of HSPA5 by HDAC6 facilitates GP78-mediated HSPA5 ubiquitination and suggest that post-translational regulation of HSPA5 protein is critical for HSPA5-mediated metastatic properties of breast cancer.

b-catenin accumulation is often found in lung tumors, but only a few patients have mutations in b-catenin gene. In addition, activated p53 downregulates b-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (b-transducin repeat-containing protein) and p53 regulation could result in b-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with b-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P ¼ 0.023B0.041). Alteration of AXIN2 was associated with poor survival in early stage patients (P ¼ 0.016). Low expression of AXIN2 and betaTrCP was significantly associated with promoter hypermethylation and histone deacetylation. Ectopic expression and knockdown of p53, AXIN2 and betaTrCP genes in A549 (p53 wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of b-catenin expression. Our clinical and cell model findings provide new evidence that epigenetic silencing of AXIN2/betaTrCP in the degradation complex and deregulation of p53-mediated control lead to wild-type b-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the b-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

Increased Crabp2 levels have been found in various types of cancer, and are associated with poor patients’ survival. Although Crabp2 is found to be overexpressed in lung cancer, its role in metastasis of lung cancer is unclear. In this study, Crabp2 was overexpressed in high-metastatic C10F4 than low-metastatic lung cancer cells. Analysis of clinical samples revealed that high CRABP2 levels were correlated with lymph node metastases, poor overall survival, and increased recurrence. Knockdown of Crabp2 decreased migration, invasion, anoikis resistance, and in vivo metastasis. Crabp2 was co-immunoprecipitated with HuR, and overexpression of Crabp2 increased HuR levels, which promoted integrin β1/FAK/ERK signaling. Inhibition of HuR or integrin β1/FAK/ERK signaling reversed the promoting effect of Crabp2 in migration, invasion, and anoikis resistance. Knockdown of Crabp2 further inhibited the growth of cancer cells as compared with that by gemcitabine or irinotecan alone. The expression of Crabp2 in human lung tumors was correlated with stress marker CHOP. In conclusion, our findings have identified the promoting role of Crabp2 in anoikis resistance and metastasis. CRABP2 may serve as a prognostic marker and targeting CRABP2 may be exploited as a modality to reduce metastasis.

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Background:Oral cancer metastasis is a devastating process that contributes to poor prognosis and high mortality, yet its detailed underlying mechanisms remain unclear. Here, we aimed to evaluate metastasis-specific markers in oral cancer and to provide comprehensive recognition concerning functional roles of the specific target in oral cancer metastasis.Methods:Lectin, galactoside-binding, soluble, 1 (LGALS1) was identified by secretomic analysis. LGALS1 expression of patient samples with oral cancer on the tissue microarray were examined by immunochemical (IHC) staining. Small interfering RNA (siRNA)-mediated knockdown of LGALS1 revealed the role of LGALS1 in oral cancer metastasis in vitro and in vivo.Results:LGALS1 was observed to be upregulated in highly invasive oral cancer cells, and elevated LGALS1 expression was correlated with cancer progression and lymph node metastasis in oral cancer tissue specimens. Functionally, silencing LGALS1 resulted in suppressed cell growth, wound healing, cell migration, and cell invasion in oral cancer cells in vitro. Knockdown of LGALS1 in highly invasive oral cancer cells dramatically inhibited lung metastasis in an in vivo mouse model. Mechanistic studies suggested p38 mitogen-activated protein kinase (MAPK) phosphorylation, upregulated MMP-9, and mesenchymal phenotypes of epithelial-mesenchymal transition (EMT) in highly invasive oral cancer cells, whereas siRNA against LGALS1 resulted in the inactivation of p38 MAPK pathway, downregulated MMP-9, and EMT inhibition.Conclusions:These findings demonstrate that elevated LGALS1 is strongly correlated with oral cancer progression and metastasis, and that it could potentially serve as a prognostic biomarker and an innovative target for oral cancer therapy.

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This study introduces a fuzzy linear control design method for nonlinear systems with optimal H 1 robustness performance. First, the Takagi and Sugeno fuzzy linear model is employed to approximate a nonlinear system. Next, based on the fuzzy linear model, a fuzzy controller is developed to stabilize the nonlinear system, and at the same time the effect of external disturbance on control performance is attenuated to a minimum level. Thus based on the fuzzy linear model, H 1 performance design can be achieved in nonlinear control systems. In the proposed fuzzy linear control method, the fuzzy linear model provides rough control to approximate the nonlinear control system, while the H 1 scheme provides precise control to achieve the optimal robustness performance. Linear matrix inequality (LMI) techniques are employed to solve this robust fuzzy control problem. In the case that state variables are unavailable, a fuzzy observer-based H 1 control is also proposed to achieve a robust optimization design for nonlinear systems. A simulation example is given to illustrate the performance of the proposed design method.Index Terms-H 1 robust control, linear matrix inequality, nonlinear fuzzy observer, Takagi-Sugeno fuzzy control.