Laszlo Jakab

Down-regulation of canonical and up-regulation of non-canonical Wnt signalling in the carcinogenic process of squamous cell lung carcinoma.

The majority of lung cancers (LC) belong to the non-small cell lung carcinoma (NSCLC) type. The two main NSCLC sub-types, namely adenocarcinoma (AC) and squamous cell carcinoma (SCC), respond differently to therapy. Whereas the link between cigarette smoke and lung cancer risk is well established, the relevance of non-canonical Wnt pathway up-regulation detected in SCC remains poorly understood. The present study was undertaken to investigate further the molecular events in canonical and non-canonical Wnt signalling during SCC development. A total of 20 SCC and AC samples with matched non-cancerous controls were obtained after surgery. TaqMan array analysis confirmed up-regulation of non-canonical Wnt5a and Wnt11 and identified down-regulation of canonical Wnt signalling in SCC samples. The molecular changes were tested in primary small airway epithelial cells (SAEC) and various lung cancer cell lines (e.g. A549, H157, etc). Our studies identified Wnt11 and Wnt5a as regulators of cadherin expression and potentiated relocation of β-catenin to the nucleus as an important step in decreased cellular adhesion. The presented data identifies additional details in the regulation of SCC that can aid identification of therapeutic drug targets in the future.

Alteration in the Wnt microenvironment directly regulates molecular events leading to pulmonary senescence

In the aging lung, the lung capacity decreases even in the absence of diseases. The progenitor cells of the distal lung, the alveolar type II cells (ATII), are essential for the repair of the gas‐exchange surface. Surfactant protein production and survival of ATII cells are supported by lipofibroblasts that are peroxisome proliferator‐activated receptor gamma (PPARγ)‐dependent special cell type of the pulmonary tissue. PPARγ levels are directly regulated by Wnt molecules; therefore, changes in the Wnt microenvironment have close control over maintenance of the distal lung. The pulmonary aging process is associated with airspace enlargement, decrease in the distal epithelial cell compartment and infiltration of inflammatory cells. qRT–PCR analysis of purified epithelial and nonepithelial cells revealed that lipofibroblast differentiation marker parathyroid hormone‐related protein receptor (PTHrPR) and PPARγ are reduced and that PPARγ reduction is regulated by Wnt4 via a β‐catenin‐dependent mechanism. Using a human in vitro 3D lung tissue model, a link was established between increased PPARγ and pro‐surfactant protein C (pro‐SPC) expression in pulmonary epithelial cells. In the senile lung, both Wnt4 and Wnt5a levels increase and both Wnt‐s increase myofibroblast‐like differentiation. Alteration of the Wnt microenvironment plays a significant role in pulmonary aging. Diminished lipo‐ and increased myofibroblast‐like differentiation are directly regulated by specific Wnt‐s, which process also controls surfactant production and pulmonary repair mechanisms.

The effect of the Progesterone-Induced Blocking Factor (PIBF) on E-cadherin expression, cell motility and invasion of primary tumour cell lines

In addition to being immunomodulatory, Progesterone-Induced Blocking Factor (PIBF) plays a role in cell cycle regulation and invasion. The full length protein is associated with the pericentriolar satellites and as such, it is crucial for maintaining the integrity of spindle poles during mitosis. Another suggestive evidence for the involvement of PIBF in tumour progression is the fact that the PIBF gene has been identified on chromosome 13 in the region associated with breast cancer susceptibility. Earlier we showed that PIBF differentially regulates the invasiveness of trophoblast and tumour cell lines. The aim of the present study was to further investigate the role of PIBF in tumour development, using primary ovarian- (OC) and primary lung carcinoma (LC) cell cultures, and JEG-3 choriocarcinoma cell line. In the cultured cells PIBF was knocked down by siRNA treatment, and the impact of PIBF deficiency on MMP-9 activity and E-cadherin expression as well as on invasive and migratory capacity of the cells was tested. In conditioned media of PIBF-deficient JEG-3 cells, LC cells and OC cells MMP-9 activity was reduced to 36% 35%, and 65% respectively compared to controls. Though PIBF knock down did not affect migration, in JEG-3 cells, LC primary cells and OC primary cells PIBF deficiency resulted 20%, 50% and 50% decrease of invasion respectively. PIBF silencing resulted in increased E-cadherin expression, suggesting that by down regulating E-cadherin expression, PIBF might interfere with the cell-cell adhesion mechanisms and by increasing MMP activity induced extracellular matrix degradation, facilitates the invasion of tumour cells.

The use of a smartphone application for fast lung cancer risk assessment

OBJECTIVES The overall prognosis of lung cancer is poor: Only every 8 patient survives 5 years after diagnosis. This outcome is partly attributable to late diagnosis. To implement a screening program for early diagnosis, selection of high-risk individuals is essential. Our aim was to construct a personalized lung cancer risk assessment tool using geographic localization to lead the high-risk individuals to the local health care provider. METHODS A smartphone application was created for Android and iOS mobile platforms using a risk assessment questionnaire. The software provides immediate classification into low, moderate and high-risk groups. The high-risk group is directed to the nearest screening centre based on GPS location. The complete test data set is recorded on a collection server database for further analysis. RESULTS The application was downloaded 13 890 times and completed by 89 500 persons over a period of 20 months. The mean age of the tested users was 36.91 years (9-93 years); the majority were men living in an urban area (62.3%). The test was completed by 38 850 active smokers and 26 710 persons who reported having already quit smoking, resulting in 30 072 moderate and 10 740 high-risk users. CONCLUSIONS This free application is an active communication tool for most smartphone owners. It helps those who might need further medical attention. The affected users can be easily connected and localized via the smartphone, which helps recruit individuals into screening programs.