Identification and Validation of Leucine-rich α-2-glycoprotein 1 as a Noninvasive Biomarker for Improved Precision in Prostate Cancer Risk Stratification.

BACKGROUND: More accurate risk assessments are needed to improve prostate cancer management. OBJECTIVE: To identify blood-based protein biomarkers that provided prognostic information for risk stratification. DESIGN SETTING AND PARTICIPANTS: Mass spectrometry was used to identify biomarker candidates from blood, and validation studies were performed in four independent cohorts retrospectively collected between 1988 and 2015. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome objectives were progression-free survival, prostate cancer-specific survival (PCSS), and overall survival. Statistical analyses to assess survival and model performance were performed. RESULTS AND LIMITATION: Serum leucine-rich α-2-glycoprotein 1 (LRG1) was found to be elevated in fatal prostate cancer. LRG1 provided prognostic information independent of metastasis and increased the accuracy in predicting PCSS, particularly in the first 3 yr. A high LRG1 level is associated with an average of two-fold higher risk of disease-progression and mortality in both high-risk and metastatic patients. However, our study design, with a retrospective analysis of samples spanning several decades back, limits the assessment of the clinical utility of LRG1 in today's clinical practice. Thus, independent prospective studies are needed to establish LRG1 as a clinically useful biomarker for patient management. CONCLUSIONS: High blood levels of LRG1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer, and LRG1 increased the accuracy of risk stratification of prostate cancer patients. PATIENT SUMMARY: High blood levels of leucine-rich α-2-glycoprotein 1 are unfavourable in newly diagnosed high-risk and metastatic prostate cancer

TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells

Background TWIST1 plays a key role in EMT-mediated tumor invasion and metastasis. Since bone metastasis is a hallmark of advanced prostate cancer and is detected in at least 85% of patients who die of this disease, it is of great importance to understand the regulation of the cellular signaling pathways involved in the metastatic process. Methods Prostatic cell lines were analyzed using real time RT-PCR, chromatin immunoprecipitations (ChIP) and transfection of siRNA’s and reporter constructs. Results We report in this paper that TWIST1 is an androgen-regulated gene under tight regulation of NKX3-1. Androgens repress the expression of TWIST1 via NKX3-1, which is a prostate–specific tumor suppressor that is down-regulated in the majority of metastatic prostate tumors. We show that NKX3-1 binds to the TWIST1 promoter and that NKX3-1 over-expression reduces the activity of a TWIST1 promoter reporter construct, whereas NKX3-1 siRNA up-regulates endogenous TWIST1 mRNA in prostate cancer cells. Conclusion Our finding that NKX3-1 represses TWIST1 expression emphasizes the functional importance of NKX3-1 in regulating TWIST1 expression during prostate cancer progression to metastatic disease

Distinct but overlapping domains of AKAP95 are implicated in chromosome condensation and condensin targeting

A-kinase (or PKA)-anchoring protein AKAP95 is a zinc-finger protein implicated in mitotic chromosome condensation by acting as a targeting molecule for the condensin complex. We have identified determinants of chromatin-binding, condensin-targeting and chromosome-condensation activities of AKAP95. Binding of AKAP95 to chromatin is conferred by residues 387–450 and requires zinc finger ZF1. Residues 525–569 are essential for condensation of AKAP95-free chromatin and condensin recruitment to chromosomes. Mutation of either zinc finger of AKAP95 abolishes condensation. However, ZF1 is dispensable for condensin targeting, whereas the C-terminal ZF2 is required. AKAP95 interacts with Xenopus XCAP-H condensin subunit in vitro and in vivo but not with the human hCAP-D2 subunit. The data illustrate the involvement of overlapping, but distinct, domains of AKAP95 for condensin recruitment and chromosome condensation and argue for a key role of ZF1 in chromosome condensation and ZF2 in condensin targeting. Moreover, condensin recruitment to chromatin is not sufficient to promote condensation

Levels and prognostic impact of circulating markers of inflammation, endothelial activation and extracellular matrix remodelling in patients with lung cancer and chronic obstructive pulmonary disease

Background The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown. Methods Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays. Results Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status. Conclusion Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis