35 research outputs found
Alternative splicing variant of the hypoxia marker carbonic anhydrase IX expressed independently of hypoxia and tumour phenotype
CA IX is a hypoxia-induced, cancer-associated carbonic anhydrase isoform with functional involvement in pH control and cell adhesion. Here we describe an alternative splicing variant of the CA9 mRNA, which does not contain exons 8–9 and is expressed in tumour cells independently of hypoxia. It is also detectable in normal tissues in the absence of the full-length transcript and can therefore produce false-positive data in prognostic studies based on the detection of the hypoxia- and cancer-related CA9 expression. The splicing variant encodes a truncated CA IX protein lacking the C-terminal part of the catalytic domain. It shows diminished catalytic activity and is intracellular or secreted. When overexpressed, it reduces the capacity of the full-length CA IX protein to acidify extracellular pH of hypoxic cells and to bind carbonic anhydrase inhibitor. HeLa cells transfected with the splicing variant cDNA generate spheroids that do not form compact cores, suggesting that they fail to adapt to hypoxic stress. Our data indicate that the splicing variant can functionally interfere with the full-length CA IX. This might be relevant particularly under conditions of mild hypoxia, when the cells do not suffer from severe acidosis and do not need excessive pH control
Synthetic lethal targeting of oncogenic transcription factors in acute leukemia by PARP inhibitors
Acute myeloid leukemia (AML) is mostly driven by oncogenic transcription factors,
which have been classically viewed as intractable targets using small molecule inhibitor
approaches. Here, we demonstrate that AML driven by repressive transcription factors
including AML1-ETO and PML-RARα are extremely sensitive to Poly (ADP-ribose)
Polymerase (PARP) inhibitor (PARPi), in part due to their suppressed expression of key
homologous recombination genes and thus compromised DNA damage response (DDR).
In contrast, leukemia driven by MLL fusions with dominant transactivation ability is
proficient in DDR and insensitive to PARP inhibition. Intriguing, depletion of an MLL
downstream target, Hoxa9 that activates expression of various HR genes, impairs DDR
and sensitizes MLL leukemia to PARPi. Conversely, Hoxa9 over-expression confers
PARPi resistance to AML1-ETO and PML-RARα transformed cells. Together, these
studies describe a potential utility of PARPi-induced synthetic lethality for leukemia
treatment and reveal a novel molecular mechanism governing PARPi sensitivity in AML
Carbonic Anhydrase IX Expression is Associated with Favorable Prognostic Factors in Small Intestinal Carcinoma
Epicardial adipose tissue and cardiometabolic risk factors in overweight and obese children and adolescents
Study of retention behavior of selected amino acid enantiomers by HRGC with modified cyclodextrins.
Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers
Eighteenth International Symp. on Capillary Chromatography, Riva del Garda, Italy 20-24 May 1996, Vol.1, 76-83. Ed. P. Sandra, Publ. Hiithig, Heidelberg, Germany.
Design, synthesis, and antitumor screening of certain novel tetrahydroquinoline sulfonamides
Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas
Contains fulltext :
118484.pdf (publisher's version ) (Open Access)Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e.g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r = 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies