Weiqi Lu

Foxo3a Expression Is a Prognostic Marker in Breast Cancer

The forkhead box transcription factor Foxo3a has been implicated to play a critical role in various cancers by suppressing tumor growth. Recent studies have identified Foxo3a as a key regulator of Estrogen Receptor-α (ERα). In the present study, we examined the expression of Foxo3a, and investigated its clinical significance and correlation with ER and prognostic role in patients with breast cancer. Immunohistochemical analysis was performed on tumors from 70 breast cancer patients. Interpretable Foxo3a expression was analyzed along with major clinicopathologic variables, and a comparison was made with corresponding 5-year clinical follow-up data. Foxo3a protein expression correlated with ER positivity (P<0.001), histologic grade (1, 2) (P = 0.002), axillary lymph node negativity (P<0.001) and TNM stage (1, 2) (P<0.001). Moreover, the Kaplan-Meier survival curves of the study population showed that a high expression level of Foxo3a was significantly correlated with long-term survival (P<0.0001). In a multivariate analysis, Foxo3a expression was identified as a favorable independent prognostic factor in overall survival (P = 0.038). In conclusion, our results indicated that Foxo3a expression is a favorable prognostic marker in breast cancer. In addition, Foxo3a staining could potentially be used in patient stratification in conjunction with other prognostic markers.

Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease that is primarily characterized by multiple café au-lait spots (CALs) and skin neurofibromas, which are attributed to defects in the tumor suppressor NF1. Because of the age-dependent presentation of NF1, it is often difficult to make an early clinical diagnosis. Moreover, identifying genetic alterations in NF1 patients represents a complex challenge. Currently, there are no effective detective methods, and no comprehensive NF1 mutation data are available for mainland China. We screened 109 Chinese patients from 100 families with NF1-like phenotypes (e.g., CALs, neurofibromas, etc.) using Sanger sequencing, multiplex ligation-dependent probe amplification and cDNA sequencing. NF1 mutations were identified in 97 individuals, among which 34 intragenic mutations have not previously been reported. Our exhaustive mutational analysis detected mutations in 89% (89/100) of the NF1-like probands and 93% (70/75) of subjects fulfilling the National Institutes of Health (NIH) criteria. Our findings indicate that individuals who exclusively present with multiple CALs exhibit a high possibility (76%) of having NF1 and show a significantly lower mutation rate (p = 0.042) compared with subjects who fulfill the NIH criteria, providing clinicians with the information that subjects only with multiple CALs harbor a considerable possibility (24%) of being attributed to other comparable diseases.

PDK1 induces JunB, EMT, cell migration and invasion in human gallbladder cancer.

The protein 3-phosphoinositide-dependent protein kinase 1 (PDK1) is upregulated in cancer. Here we showed that PDK1 stimulated cell proliferation, invasion and metastasis in gallbladder cancer (GBC), by inducing JunB and epithelial–mesenchymal transition. JunB levels were increased in GBC samples and positively correlated with PDK1 levels in tumors. High levels of JunB predicted poor overall survival in GBC patients. Thus, PDK1 functions as a tumor promoter in human GBC by upregulating JunB.

Nemo-Like Kinase Associated with Proliferation and Apoptosis by c-Myb Degradation in Breast Cancer

Nemo-like kinase (NLK), a mediator of the Wnt signaling pathway, binds directly to c-Myb, leading to its phosphorylation, ubiquitination and proteasome-dependent degradation. NLK was significantly downregulated in the breast cancer tissues compared to corresponding normal tissues. NLK expression was negatively correlated with c-Myb expression. NLK suppressed proliferation, induced apoptosis and mediated c-Myb degradation in MCF-7 cells via a mechanism that seems to involve c-myc and Bcl2. These findings might provide a novel target for therapeutic intervention in patients with breast cancer.

HDAC1 promoted migration and invasion binding with TCF12 by promoting EMT progress in gallbladder cancer

The identification of prognostic markers for gallbladder cancer is needed for clinical practice. Histone deacetylases (HDACs) play an important role in tumor development and progression by modifying histone and non-histone proteins. However, the expression of HDAC1 in patients with gallbladder cancer is still unknown. Here, we reported that HDAC1 expression was elevated in cancerous tissue and correlated with lymph node metastasis and poorer overall survival in patients with GBC. Knockdown of HDAC1 using lentivirus delivery of HDAC1-specific shRNA abrogated the migration and invasion of GBC cells in vitro. TCF-12, as the HDAC1 binding protein, has also correlates with poor prognosis in GBC patients. And there is a positive correlation between HDAC1 and TCF-12 which leading the high invasion and migration ability of GBC cells. Taken together, our data suggested that HDAC1 and TCF-12 are a potential prognostic maker and may be a molecular target for inhibiting invasion and metastasis in GBC.

Combination of thiazolidinedione and hydralazine suppresses proliferation and induces apoptosis by PPARγ up-expression in MDA-MB-231 cells.

No proven targeted therapy is currently available for the treatment of triple-negative breast cancer (TNBC). Ligand activation of peroxisome-activated receptor (PPAR)γ induces antitumor effects in cancer but not obviously in TNBC. In TNBC cells, combined treatment with thiazolidinedione and demethylation drugs Hydralazine up-regulated protein and mRNA levels of PPARγ. Besides, the combination of two drugs promote antiproliferative and apoptotic effects in TNBC cells and decrease the proliferation index in the tumor xenografts. Taken together, our results suggest that multidrug regimens including a combination of Thiazolidinedione and Hydralazine may provide a therapeutic advantage in TNBC.

Expression profile of microRNAs in gastrointestinal stromal tumors revealed by high throughput quantitative RT-PCR microarray

AIM To investigate the microRNA (miRNA) expression profile in gastrointestinal stromal tumor (GIST) tissues that could serve as a novel diagnostic biomarker for GIST detection. METHODS We performed a quantitative real-time quantitative reverse transcriptase polymerase chain reaction assay to analyze the expression of 1888 miRNAs in a sample set that included 54 GIST tissue samples. RESULTS We found that dysregulation of several miRNAs may be related to the malignant potential of GISTs. Six of these miRNAs, hsa-let-7c, miR-218, miR-488#, miR-4683, miR-34c-5p and miR-4773, were selected as the final list of biomarkers to separate the malignant GISTs (M group) from the benign GISTs (B group). In addition, MiR-29b-2#, hsa-let-7c, miR-891b, miR-218, miR-204, miR-204-3p, miR-628-5p, miR-744, miR-29c#, miR-625 and miR-196a were used to distinguish between the borderline (BO group) and M groups. There were 11 common miRNAs selected to separate the benign and borderline (BB) group from the M group, including hsa-let-7c, miR-218, miR-628-5p, miR-204-3p, miR-204, miR-891b, miR-488#, miR-145, miR-891a, miR-34c-5p and miR-196a. CONCLUSION The identified miRNAs appear to be novel biomarkers to distinguish malignant from benign GISTs, which may be helpful to understand the mechanisms of GIST oncogenesis and progression, and to further elucidate the characteristics of GIST subtypes.

Lysine-specific demethylase 1 promotes tumorigenesis and predicts prognosis in gallbladder cancer

Gallbladder Cancer (GBC), characterized by invasive growth and infiltrative dissemination, is difficult to diagnose and has poor prognosis. Emerging evidence demonstrates that Lysine-Specific Demethylase 1 (LSD1) has important roles in carcinogenesis, proliferation and metastasis. We studied the roles and molecular mechanisms of LSD1 in GBC. We examined LSD1 expression in 109 paired samples of GBC and normal gallbladder tissues. We found GBC tissues had upregulated LSD1 compared with normal gallbladder tissues (P = 0.003), and its high expression was associated with tumor-node-metastasis stage (P < 0.0001), Nevins stage (P = 0.0093) and distant metastases (P = 0.0070). We found positive correlations between LSD1 expression and other proteins: epithelial–mesenchymal transition markers, C-myc and cyclin-related proteins. Inhibiting LSD1 expression in vitro impaired the proliferation and invasiveness of GBC cells and also downregulated c-myc expression and consequently inhibited GBC cell proliferation. LSD1 overexpression promotes GBC development and may be a predictor for a worsened prognosis. LSD1 may be a novel therapeutic target and prognostic tool for gallbladder cancer.

Liposarcoma miRNA signatures identified from genome-wide miRNA expression profiling.

AIMS To identify the miRNA expression profile of liposarcoma (LPS) that could facilitate detection of LPS, and provide the basis for further investigation of molecular-targeted therapeutic drugs. MATERIALS & METHODS A real-time quantitative PCR assay was performed to analyze the expression of 1888 miRNAs from 25 LPS tumor tissue samples, 16 samples of adipose tissue adjacent to the tumors and 18 normal adipose tissue samples from patients with LPS. RESULTS Ten dysregulated miRNAs were identified that effectively distinguished LPS tissue from adipose tissue and benign lipoma tissue, and LPS tumor tissues from normal adipose tissues in LPS patients. Furthermore, the expression profiles of miRNAs could also classify the subtype of LPS. CONCLUSION The identified miRNAs appear to be novel biomarkers for the detection of LPS, and may contribute to an understanding of the mechanisms of LPS tumorigenesis and its development, and further elucidate the characteristics of LPS subtypes.

Recurrent abdominal liposarcoma: analysis of 19 cases and prognostic factors.

AIM To evaluate the clinical outcome of re-operation for recurrent abdominal liposarcoma following multidisciplinary team cooperation. METHODS Nineteen consecutive patients who had recurrent abdominal liposarcoma underwent re-operation by the retroperitoneal sarcoma team at our institution from May 2009 to January 2012. Patient demographic and clinical data were reviewed retrospectively. Multidisciplinary team discussions were held prior to treatment, and re-operation was deemed the best treatment. The categories of the extent of resection were as follows: gross total resection (GTR), palliative resection and partial resection. Surgical techniques were divided into discrete lesion resection and combined contiguous multivisceral resection (CMR). Tumor size was determined as the largest diameter of the specimen. Patients were followed up at approximately 3-monthly intervals. For survival analysis, a univariate analysis was performed using the Kaplan-Meier method, and a multivariate analysis was performed using the Cox proportional hazards model. RESULTS Nineteen patients with recurrent abdominal liposarcoma (RAL) underwent 32 re-operations at our institute. A total of 51 operations were reviewed with a total follow-up time ranging from 4 to 120 (47.4 ± 34.2) mo. The GTR rate in the CMR group was higher than that in the non-CMR group (P = 0.034). CMR was positively correlated with intra-operative bleeding (correlation coefficient = 0.514, P = 0.010). Six cases with severe postoperative complications were recorded. Patients with tumor sizes greater than 20 cm carried a significant risk of profuse intra-operative bleeding (P = 0.009). The ratio of a highly malignant subtype (dedifferentiated or pleomorphic) in recurrent cases was higher compared to primary cases (P = 0.027). Both single-factor survival using the Kaplan-Meier model and multivariate analysis using the Cox proportional hazards model showed that overall survival was correlated with resection extent and pathological subtype (P < 0.001 and P = 0.02), however, relapse-free interval (RFI) was only correlated with resection extent (P = 0.002). CONCLUSION Close follow-up should be conducted in patients with RAL. Early re-operation for relapse is preferred and gross resection most likely prolongs the RFI.