ABSTRACT
Abnormal Sonic Hedgehog signalling leads to increased transcriptional activation of its downstream effector, glioma 2 (GLI2), which is implicated in the pathogenesis of a variety of human cancers. However, the mechanisms underlying the tumorigenic role of GLI2 remain elusive. We demonstrate that overexpression of GLI2-ß isoform, which lacks the N-terminal repressor domain (GLI2ΔN) in human keratinocytes is sufficient to induce numerical and structural chromosomal aberrations, including tetraploidy/aneuploidy and chromosomal translocations. This is coupled with suppression of cell cycle regulators p21(WAF1/CIP1) and 14-3-3σ, and strong induction of anti-apoptotic signalling, resulting in a reduction in the ability to eliminate genomically abnormal cells. Overexpression of GLI2ΔN also rendered human keratinocytes resistant to UVB-mediated apoptosis, whereas inhibition of B-cell lymphoma 2 (BCL-2) restored endogenous (genomic instability (GIN)) and exogenous (UVB) DNA damage-induced apoptosis. Thus, we propose that ectopic expression of GLI2 profoundly affects the genomic integrity of human epithelial cells and contributes to the survival of progenies with genomic alterations by deregulating cell cycle proteins and disabling the apoptotic mechanisms responsible for their elimination. This study reveals a novel role for GLI2 in promoting GIN, a hallmark of human tumors, and identifies potential mechanisms that may provide new opportunities for the design of novel forms of cancer therapeutic strategies.
Subject(s)
Apoptosis , Carcinoma, Basal Cell/metabolism , Genomic Instability , Keratinocytes/cytology , Keratinocytes/metabolism , Kruppel-Like Transcription Factors/metabolism , Nuclear Proteins/metabolism , Apoptosis/radiation effects , Carcinoma, Basal Cell/genetics , Carcinoma, Basal Cell/physiopathology , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Chromosome Aberrations , Down-Regulation , Humans , Keratinocytes/radiation effects , Kruppel-Like Transcription Factors/chemistry , Kruppel-Like Transcription Factors/genetics , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Protein Structure, Tertiary , Ultraviolet Rays , Zinc Finger Protein Gli2ABSTRACT
PURPOSE: Screening is a significant method for cancer control, nevertheless the implementation of non cost-effective screening tests at national level may constitute a major burden to health economics. The purpose of this study was to determine the cancer screening activities of a large sample of the Hellenic population, in a country with opportunistic screening practice. METHODS: A large survey on cancer screening in Greece was organized and conducted by the Panhellenic Association for Continual Medical Research (PACMeR). Screening performance of evidence-based (EB), non-evidence-based (non EB) and of undefined benefit tests was analysed. RESULTS: 7001 individuals were analysed. Eighty-eight percent of males and 93% of females stated that they were interested in cancer screening practices. Gynecological cancer screening was performed in the range of 23-38%. Colorectal cancer screening was rarely performed in both genders (1- 2%), while non-evidence-based tests were regularly performed (urinalysis 50% and chest radiography 15-18%). Full blood count and PSA measurement were widely accepted (over 45% in both genders and 19.5% in males, respectively). Sociodemographic characteristics did not influence the performance of EB tests in males while females' activities were highly influenced by such parameters. CONCLUSION: Opportunistic cancer screening in a primary health care system where national guidelines are missing may cause ambiguous results. Reconsideration of health policy in such cases is mandatory.
Subject(s)
Government Regulation , Health Policy , Health Priorities , Mass Screening/methods , Neoplasms/diagnosis , Practice Patterns, Physicians' , Primary Health Care , Unnecessary Procedures , Aged , Chi-Square Distribution , Cost-Benefit Analysis , Cross-Sectional Studies , Female , Greece , Health Care Costs , Health Policy/economics , Health Priorities/economics , Health Priorities/legislation & jurisprudence , Health Services Research , Humans , Male , Mass Screening/economics , Mass Screening/legislation & jurisprudence , Middle Aged , Practice Guidelines as Topic , Practice Patterns, Physicians'/economics , Practice Patterns, Physicians'/legislation & jurisprudence , Predictive Value of Tests , Primary Health Care/economics , Primary Health Care/legislation & jurisprudence , Surveys and Questionnaires , Unnecessary Procedures/economicsABSTRACT
Although data from literature suggest that diabetic women are frequently under screened for gynaecological cancers little is known about screening implementation for other cancers for both genders. This study investigates comprehensive cancer screening practices of diabetics as compared with non-diabetics; analyses screening patterns both by gender and level of evidence and reveals target subgroups that should be paid more attention for screening implementation. 675 diabetics vs. 5772 non-diabetic Greek individuals entered the PACMeR 02 cancer screening study. Diabetic women reported significantly lower performance for the sex-specific evidence-based cancer screening tests and digital rectal examination (DRE) as compared with non-diabetics (P < 0.05). Diabetic women older than 60 years old, of elementary education, housewives and farmers showed the lowest performance rates (P < 0.01). Prostate cancer screening was higher among diabetic men with ultrasound and DRE reaching statistical significance (P < 0.05). Subgroups analysis did not reveal a hidden relationship. Both genders of diabetics reported never performing skin examination at higher rates (P < 0.001), although screening intent is extremely low in both diabetics and non-diabetics (<1%). Evidence-based screening coverage was inconsistent in both genders independently by the diabetic status. Primary care efforts should be provided to implement presymptomatic cancer control.
