Up-regulation of 14-3-3ζ in Lung Cancer and Its Implication as Prognostic and Therapeutic Target

Abstract

A functional genomic approach integrating microarray and proteomic analyses done in our laboratory has identified 14-3-3Z as a putative oncogene whose activation was common and driven by its genomic amplification in lung adenocarcinomas. 14-3-3Z is believed to function in cell signaling, cycle control, and apoptotic death. Following our initial finding, here, we analyzed its expression in lung tumor tissues obtained from 205 patients with various histologic and stage non-small cell lung cancers (NSCLC) using immunohistochemistry and then explored the effects of specific suppression of the gene in vitro and in a xenograft model using small interfering RNA. The increased 14-3-3Z expression was positively correlated with a more advanced pathologic stage and grade of NSCLCs (P = 0.001 and P = 0.006, respectively) and was associated with overall and cancer-specific survival rates of the patients (P = 0.022 and P = 0.018, respectively). Down-regulation of 14-3-3Z in lung cancer cells led to a dose-dependent increased sensitivity to cisplatin-induced cell death, which was associated with the inhibition of cell proliferation and increased G 2 -M arrest and apoptosis. The result was further confirmed in the animal model, which showed that the A549 lung cancer cells with reduced 14-3-3Z grew significantly slower than the wild-type A549 cells after cisplatin treatment (P = 0.008). Our results suggest that 14-3-3Z is a potential target for developing a prognostic biomarker and therapeutics that can enhance the antitumor activity of cisplatin for NSCLC. [Cancer Res 2007;67(16):7901-6]

Four proteins governing overangiogenic endothelial cell phenotype in patients with multiple myeloma are plausible therapeutic targets

“…When we silenced MGECs and normal ECs, we obtained a greater protein reduction (À30% and À60%, respectively), with a progressive impairment of their angiogenic ability. Indeed, normal ECs were inhibited in viability, which agrees with the supporting role of YWHAZ to the G2-M phase transition (Fan et al, 2007). EC spreading was also inhibited in agreement with the role of the protein in cell anchorage to the matrix (Li et al, 2008).…”

A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

“…Using a functional genomic approach, we identified 14-3-3zeta as a putative oncogene whose activation was common and driven by its genomic amplification in NSCLC (8,19). The present data support our previous discoveries (8,19,(22)(23) and also demonstrate that assessing increased 14-3-3zeta copy numbers in sputum might be useful in early diagnosis of SCCs. Similarly, SKP2 was located at a genomic amplified region, 5p13 (8,19).…”

Proteomic Analysis of Differentially Expressed Proteins in Peripheral Cholangiocarcinoma

“…14-3-3 proteins have been shown to have roles in suppressing apoptosis or regulating cell survival ( [20,[39][40][41]) and these may represent a novel indicator of cancer transformation in hepatocytes or biliary epithelium. In addition to its role in regulation of apoptosis, 14-3-3 sigma protein, also known as stratifin, is now known to be secreted via exosomes and induces expression of the matrix metalloproteinases, MMP-1 and MMP-3.…”