SERPINB5 and AKAP12 -- Expression and promoter methylation of metastasis suppressor genes in pancreatic ductal adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Early metastasis and infiltration are survival limiting characteristics of pancreatic ductal adenocarcinoma (PDAC). Thus, PDAC is likely to harbor alterations in metastasis suppressor genes that may provide novel diagnostic and therapeutic opportunities. This study investigates a panel of metastasis suppressor genes in correlation to PDAC phenotype and examines promoter methylation for regulatory influence on metastasis suppressor gene expression and for its potential as a diagnostic tool.</p> <p>Methods</p> <p>Metastatic and invasive potential of 16 PDAC cell lines were quantified in an orthotopic mouse model and mRNA expression of 11 metastasis suppressor genes determined by quantitative RT-PCR. Analysis for promoter methylation was performed using methylation specific PCR and bisulfite sequencing PCR. Protein expression was determined by Western blot.</p> <p>Results</p> <p>In general, higher metastasis suppressor gene mRNA expression was not consistent with less aggressive phenotypes of PDAC. Instead, mRNA overexpression of several metastasis suppressor genes was found in PDAC cell lines vs. normal pancreatic RNA. Of the investigated metastasis suppressor genes, only higher <it>AKAP12 </it>mRNA expression was correlated with decreased metastasis (P < 0.05) and invasion scores (P < 0.01) while higher <it>SERPINB5 </it>mRNA expression was correlated with increased metastasis scores (P < 0.05). Both genes' promoters showed methylation, but only increased <it>SERPINB5 </it>methylation was associated with loss of mRNA and protein expression (P < 0.05). <it>SERPINB5 </it>methylation was also directly correlated to decreased metastasis scores (P < 0.05).</p> <p>Conclusions</p> <p><it>AKAP12 </it>mRNA expression was correlated to attenuated invasive and metastatic potential and may be associated with less aggressive phenotypes of PDAC while no such evidence was obtained for the remaining metastasis suppressor genes. Increased <it>SERPINB5 </it>mRNA expression was correlated to increased metastasis and mRNA expression was regulated by methylation. Thus, <it>SERPINB5 </it>methylation was directly correlated to metastasis scores and may provide a diagnostic tool for PDAC.</p

Somatic LKB1 Mutations Promote Cervical Cancer Progression

Human Papilloma Virus (HPV) is the etiologic agent for cervical cancer. Yet, infection with HPV is not sufficient to cause cervical cancer, because most infected women develop transient epithelial dysplasias that spontaneously regress. Progression to invasive cancer has been attributed to diverse host factors such as immune or hormonal status, as no recurrent genetic alterations have been identified in cervical cancers. Thus, the pressing question as to the biological basis of cervical cancer progression has remained unresolved, hampering the development of novel therapies and prognostic tests. Here we show that at least 20% of cervical cancers harbor somatically-acquired mutations in the LKB1 tumor suppressor. Approximately one-half of tumors with mutations harbored single nucleotide substitutions or microdeletions identifiable by exon sequencing, while the other half harbored larger monoallelic or biallelic deletions detectable by multiplex ligation probe amplification (MLPA). Biallelic mutations were identified in most cervical cancer cell lines; HeLa, the first human cell line, harbors a homozygous 25 kb deletion that occurred in vivo. LKB1 inactivation in primary tumors was associated with accelerated disease progression. Median survival was only 13 months for patients with LKB1-deficient tumors, but >100 months for patients with LKB1-wild type tumors (P = 0.015, log rank test; hazard ratio = 0.25, 95% CI = 0.083 to 0.77). LKB1 is thus a major cervical tumor suppressor, demonstrating that acquired genetic alterations drive progression of HPV-induced dysplasias to invasive, lethal cancers. Furthermore, LKB1 status can be exploited clinically to predict disease recurrence

Visualisation and quantification of CV chondrite petrography using micro-tomography

Micro-computed tomography is a non-destructive technique that allows the study of 3D meteorite petrography. The technique produces a unique and instructive visualisation of the meteorite for quantifying its components. We studied the overall petrography of the two CV chondrites Allende and Mokoia to constrain their formation histories. A set of movies and stereographic images detail the 3D petrography. Component modal abundances agree with previous reports and modal abundance differences between Allende and Mokoia support the chondrule-matrix complementarity and that chondrules and matrix formed from the same chemical reservoir. We identified two types of chondrules, a normal type and one where a normal type I or II chondrule is almost completely encapsulated by an opaque-rich layer. This layer was probably acquired during a late stage condensation process. The appearance of opaques in chondrules and matrix is different, not supporting a genetic relationships between these. Low abundances of compound chondrules (1.75 vol% in Allende and 2.50 vol% in Mokoia) indicate low chondrule densities and/or low relative component velocities in chondrule formation regions. Porosities on a scale <10-20 μm allowed for only local aqueous alteration processes on the meteorite parent bodies. © 2012 Elsevier Ltd

Visualisation and quantification of CV chondrite petrography using micro-tomography

Micro-computed tomography is a non-destructive technique that allows the study of 3D meteorite petrography. The technique produces a unique and instructive visualisation of the meteorite for quantifying its components. We studied the overall petrography of the two CV chondrites Allende and Mokoia to constrain their formation histories. A set of movies and stereographic images detail the 3D petrography. Component modal abundances agree with previous reports and modal abundance differences between Allende and Mokoia support the chondrule-matrix complementarity and that chondrules and matrix formed from the same chemical reservoir. We identified two types of chondrules, a normal type and one where a normal type I or II chondrule is almost completely encapsulated by an opaque-rich layer. This layer was probably acquired during a late stage condensation process. The appearance of opaques in chondrules and matrix is different, not supporting a genetic relationships between these. Low abundances of compound chondrules (1.75 vol% in Allende and 2.50 vol% in Mokoia) indicate low chondrule densities and/or low relative component velocities in chondrule formation regions. Porosities on a scale <10-20 μm allowed for only local aqueous alteration processes on the meteorite parent bodies. © 2012 Elsevier Ltd