Xiaoju Wang

Development of a multiplex autoantibody test for detection of lung cancer.

Lung cancer is the leading cause of cancer-related deaths for both men and women. Early diagnosis of lung cancer has a 5-year survival rate of 48.8%, however, nearly 35% of stage I patients relapses after surgical resection, thus portending a poor prognosis. Therefore, detecting lung cancer in early stage and further identifying the high-risk patients would allow the opportunity to provide adjuvant therapy and possibly increase survival. There is considerable evidence that the immune system produces an autoantibody response to neoplastic cells. The detection of such autoantibodies has been shown to have diagnostic and prognostic value. Here we took advantage of the high-throughput Luminex technique to multiplex a total of 14 tumor-associated autoantigens to detect the autoantibody from the patients sera. The 14 antigens were expressed by in vitro transcription/translation system with HaloTag at N-terminus. The fusion proteins were then covalently immobilized onto the Luminex microspheres conjugated by the halo-link ligand, thus eliminating the protein purification procedure. Sera samples from cancer patients and healthy controls were interacted with the microsphere-antigen complex to measure the autoantibodies. We have developed a quick multiplex detection system for measuring autoantibody signature from patient sera with minimal cross-reaction. A panel of seven autoantibody biomarkers has generated an AUC>80% in distinguishing the lung cancers from healthy controls. This study is the first report by combining Luminex platform and HaloTag technology to detect humoral immune response in cancer patients. Due to the flexibility of the Luminex technology, this approach can be applied to others conditions such as infectious, neurological, and metabolic diseases. One can envision that this multiplex Luminex system as well as the panel of seven biomarkers could be used to screen the high-risk population with subsequent CT test based on the blood test result.

Multiplexed Serum Biomarkers for the Detection of Lung Cancer

Currently, there is no available biomarker for lung cancer diagnosis. Here we recruited 844 lung cancer patients and 620 healthy participants from six hospitals. A total of four serum proteins was identified and subsequently assessed in the training and validation cohorts. The concentrations of four serum proteins were found to be significantly higher in lung cancer patients compared with healthy participants. The area under the curve (AUC) for the 4-biomarker were 0.86 in the training cohort, and 0.87 in the validation cohort. The classification improved to a corrected AUC of 0.90 and 0.89 respectively following addition of sex, age and smoking status. Similar results were observed for early-stage lung cancer. Remarkably, in a blinded test with a suspicious pulmonary nodule, the adjusted prediction model correctly discriminated the patients with 86.96% sensitivity and 98.25% specificity. These results demonstrated the 4-biomarker panel improved lung cancer prediction beyond that of known risk factors. Moreover, the biomarkers were valuable in differentiating benign nodules which will remain indolent from those that are likely to progress and therefore might serve as an adjuvant diagnosis tool for LDCT scanning.

An Overview on Small Molecule Inhibitors of BRD4

BRD4, an epigenetic regulator that recognizes and binds the acetylated lysine residues in histone, has been reported as a potential therapeutic target for cancers. Since the first BRD4 inhibitor JQ1 developed in 2010, numerous BRD4 inhibitors have been discovered in past five years. In this review, we have systematically summarized a series of BRD4 binding compounds, which are divided into five categories based on the similarity of their chemical structures and respectively referred as JQ1 derivatives, tetrahydroquinoline derivatives, 3,5- dimethylisoxazole derivatives, 2-thiazolidinone derivatives and others. The binding affinities for each class of compounds are also discussed.

Brother of Regulator of Imprinted Sites (BORIS) suppresses apoptosis in colorectal cancer

Identifying oncogenes that promote cancer cell proliferation or survival is critical for treatment of colorectal cancer. The Brother of Regulator of Imprinted Sites (BORIS) is frequently expressed in most types of cancer, but rarely in normal tissues. Aberrantly expressed BORIS relates to colorectal cancer, but its function in colorectal cancer cells remains unclear. In addition, previous studies indicated the significance of cytoplasm-localized BORIS in cancer cells. However, none of them investigated its function. Herein, we investigated the functions of BORIS in cancer cell proliferation and apoptosis and the role of cytoplasm-localized BORIS in colorectal cancer. BORIS expression correlated with colorectal cancer proliferation. BORIS overexpression promoted colorectal cancer cell growth, whereas BORIS knockdown suppressed cell proliferation. Sensitivity of colorectal cancer cells to 5-fluorouracil (5-FU) was inversely correlated with BORIS expression. These data suggest that BORIS functions as an oncogene in colorectal cancer. BORIS silencing induced reactive oxygen species (ROS) production and apoptosis, whereas BORIS supplementation inhibited apoptosis induced by BORIS short interfering RNA (siRNA), hydrogen peroxide (H2O2) or 5-FU. Introduction of BORIS-ZFdel showed that cytoplasmic localization of BORIS inhibited apoptosis but not ROS production. Our study highlights the anti-apoptotic function of BORIS in colorectal cancer.

Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor

Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs.

WBSCR22 confers oxaliplatin resistance in human colorectal cancer

Human WBSCR22 gene is involved in tumor metastasis, cell growth and invasion, however, its role in chemosensitivity to antitumor agents remains unknown. In this study, we analyzed the TCGA cohort and found the expression of WBSCR22 was significantly elevated in human colorectal cancer (CRC) tissue. WBSCR22 could be served as an independent risk predictor for overall survival (OS), and up-regulated WBSCR22 could predict unfavorable OS for CRC patients. Knockdown of WBSCR22 significantly sensitized CRC cells to oxaliplatin in vitro and in vivo, while overexpression of WBSCR22 led to cellular resistance to oxaliplatin treatment. Although WBSCR22 knockdown did not change cell cycle, it increased the oxaliplatin-induced cellular apoptosis. WBSCR22 knockdown augmented the oxaliplatin-induced intracellular reactive oxygen species (ROS) production and ROS-induced 8-oxoguanine (8-oxoG) oxidative lesion accumulation, likely sensitizing oxaliplatin treatment. These results demonstrate that WBSCR22 is involved in CRC resistance to oxaliplatin, suggesting WBSCR22 may represent a novel oxaliplatin resistance biomarker as well as a potentail target for CRC therapeutics.

Notch1 suppresses prostate cancer cell invasion via the metastasis‑associated 1‑KiSS‑1 metastasis‑suppressor pathway

Notch1 is a type-1 transmembrane receptor which has been demonstrated to be involved in proliferation in various organisms. A number of studies have proposed that Notch signaling may be aberrantly activated, thus contributing to development, invasion and metastasis in a variety of human cancers. In the present study, the function and mechanism of Notch1 in human prostate cancer (PCa) LNCaP cells in vitro was investigated. Notch1 and cleaved-Notch1 expression were evaluated in human PCa cell lines, including LNCaP, PC-3 and DU 145, and the human prostate epithelial RWPE-1 cell line. LNCaP cells were transfected with Notch1-targeting short hairpin RNAs (shRNAs) and the level of proliferation, the ability to invade and the expression of genes associated with cancer cell invasion were subsequently investigated. Notch1 was highly expressed in LNCaP, PC-3 and DU 145 cells compared with RWPE-1 cells, while cleaved-Notch1 was expressed in LNCaP, PC-3 and DU 145 cells, and only to a minimal extent in RWPE-1 cells. Knockdown of Notch1 by shRNA in LNCaP cells markedly decreased cell invasion through Matrigel and inhibited cell proliferation 48 h following transfection. Reverse transcription-quantitative polymerase chain reaction analysis indicated that Notch1-knockdown resulted in a significant reduction of metastasis-associated 1 (MTA1) and increase of KiSS-1 metastasis-suppressor (KISS-1), mitogen-activated protein kinase 4 (MKK4) and cluster of differentiation 82 (KAI1). The present data demonstrated that expression of Notch1 was significantly associated with the invasion of prostate cancer. Knockdown of Notch1 decreased the invasive ability of LNCaP cells, which may be caused by downregulating MTA1 and upregulating KISS-1, MKK4 and KAI1. These findings indicated that targeting Notch1 may provide a novel method of suppressing or treating metastasis in prostate cancer.

E-26 Transformation-specific Related Gene Expression and Outcomes in Cytogenetically Normal Acute Myeloid Leukemia: A Meta-analysis.

Background: The E-26 transformation-specific related gene (ERG) is frequently expressed in cytogenetically normal acute myeloid leukemia (CN-AML). Herein, we performed a meta-analysis to investigate the relationship between the prognostic significance of ERG expression and CN-AML. Methods: A systematic review of PubMed database and other search engines were used to identify the studies between January 2005 and November 2016. A total of 667 CN-AML patients were collected from seven published studies. Of the 667 patients underwent intensive chemotherapy, 429 had low expression of ERG and 238 had high expression of ERG. Summary odds ratio (OR) and the 95% confidence interval (CI) for the ERG expression and CN-AML were calculated using fixed- or random-effects models. Heterogeneity was assessed using Chi-squared-based Q-statistic test and I2 statistics. All statistical analyses were performed using R.3.3.1 software packages (R Foundation for Statistical Computing, Vienna, Austria) and RevMan5.3 (Cochrane Collaboration, Copenhagen, Denmark). Results: Overall, patients with high ERG expression had a worse relapse (OR = 2.5127, 95% CI: 1.5177–4.1601, P = 0.0003) and lower complete remission (OR = 0. 3495, 95% CI: 0.2418–0.5051, P < 0.0001). With regard to the known molecular markers, both internal tandem duplications of the fms-related tyrosine kinase 3 gene (OR = 3.8634, 95% CI: 1.8285–8.1626, P = 0.004) and brain and acute leukemia, cytoplasmic (OR = 3.1538, 95% CI: 2.0537–4.8432, P < 0.0001) were associated with the ERG expression. In addition, the results showed a statistical significance between French-American-British (FAB) classification subtype (minimally differentiated AML and AML without maturation, OR = 4.7902, 95% CI: 2.7772–8.2624, P < 0.0001; acute monocytic leukemia, OR = 0.2324, 95% CI: 0.0899–0.6006, P = 0.0026) and ERG expression. Conclusion: High ERG expression might be used as a strong adverse prognostic factor in CN-AML.