Activation of GATA binding protein 6 (GATA6) sustains oncogenic lineage-survival in esophageal adenocarcinoma.

Gene amplification is a tumor-specific event during malignant transformation. Recent studies have proposed a lineage-dependency (addiction) model of human cancer whereby amplification of certain lineage transcription factors predisposes a survival mechanism in tumor cells. These tumor cells are derived from tissues where the lineage factors play essential developmental and maintenance roles.

Curcumin promotes apoptosis, increases chemosensitivity, and inhibits nuclear factor kappaB in esophageal adenocarcinoma.

The transcription factor, nuclear factor kappaB (NF-kappaB), plays a central role as a key mediator of cell survival and proliferation, and its activation may confer increased tumor chemoresistance. Curcumin, an orally available naturally occurring compound, has been shown to inhibit NF-kappaB and has a potential role in cancer chemoprevention. We investigated the effects of curcumin on NF-kappaB activity, on cell viability, and as a chemosensitizing agent with 5-fluorouracil (5-FU) or cisplatin (CDDP) in esophageal adenocarcinoma (EAC).

Decreased selenium-binding protein 1 in esophageal adenocarcinoma results from posttranscriptional and epigenetic regulation and affects chemosensitivity.

Purpose: The chemopreventive effects of selenium have been extensively examined, but its role in cancer development or as a chemotherapeutic agent has only recently been explored. Because selenium-binding protein 1 (SELENBP1, SBP1, hSP56) has been shown to bind selenium covalently and selenium deficiency has been associated with esophageal adenocarcinoma (EAC), we examined its role in EAC development and its potential effect on chemosensitivity in the presence of selenium.

Experimental Design: SELENBP1 expression level and copy number variation were determined by oligonucleotide microarrays, real-time reverse transcription-PCR, tissue microarrays, immunoblotting, and single-nucleotide polymorphism arrays.

Upregulated INHBA expression may promote cell proliferation and is associated with poor survival in lung adenocarcinoma.

Introduction: The expression, mechanisms of regulation, and functional impact of INHBA (activin A) in lung adenocarcinoma (AD) have not been fully elucidated.

Methods: INHBA expression was examined in 96 lung samples (86 ADs, 10 normal lung) using oligonucleotide microarrays and 187 lung samples (164 ADs, 6 bronchioalveolar carcinomas, and 17 normal lung) using immunohistochemistry. The proliferation of AD cell lines H460 and SKLU1 was examined with WST-1 assays after treatment with recombinant activin A, follistatin, and INHBA-targeting small-interfering RNA.

INHBA overexpression promotes cell proliferation and may be epigenetically regulated in esophageal adenocarcinoma.

Introduction: The expression, mechanisms of regulation, and functional impact of activin (INHBA) in esophageal adenocarcinoma (EAC) have not been fully defined.

Methods: INHBA expression was examined in 46 esophageal samples (nine Barrett's metaplasia (BM); seven BM/low-grade dysplasia; eight low-grade dysplasia; seven high-grade dysplasia; 15 EAC) using oligonucleotide microarrays and real-time reverse transcription-polymerase chain reaction (RT-PCR) and in 90 tissue samples (79 EAC; 8 dysplastic; 3 BM) using immunohistochemistry (IHC). The proliferation of EAC cell lines FLO and OE-33 was examined after treatment with exogenous activin.

Inhibition of UVA-induced c-Jun N-terminal kinase activity results in caspase-dependent apoptosis in human keratinocytes.

Inhibition of c-Jun N-terminal kinase (JNK) with the pharmacologic inhibitor SP600125 in UVA-irradiated HaCaT cells and human primary keratinocytes resulted in dramatic phenotypic changes indicative of cell death. These phenotypic changes correlated with caspase 8, 9 and 3 activations as well as cleavage of the caspase substrate polyADP-ribose polymerase (PARP). Morphologic analysis and analysis of sub-G0 DNA content confirmed apoptotic cell death in these keratinocytes after combination treatment.

The role of JNK and p38 MAPK activities in UVA-induced signaling pathways leading to AP-1 activation and c-Fos expression.

To further delineate ultraviolet A (UVA) signaling pathways in the human keratinocyte cell line HaCaT, we examined the potential role of mitogen-activated protein kinases (MAPKs) in UVA-induced activator protein-1 (AP-1) transactivation and c-Fos expression. UVA-induced phosphorylation of p38 and c-Jun N-terminal kinase (JNK) proteins was detected immediately after irradiation and disappeared after approximately 2 hours. Conversely, phosphorylation of extracellular signal-regulated kinase was significantly inhibited for up to 1 hour post-UVA irradiation.

The role of p38 in UVA-induced cyclooxygenase-2 expression in the human keratinocyte cell line, HaCaT.

We examined the expression of cycloxygenase-2, the rate-limiting enzyme in the production of prostaglandins, in the UVA-irradiated human keratinocyte cell line, HaCaT. UVA induced a dose-dependent increase in COX-2 at the protein level at 2 and 4 h post-irradiation and at the mRNA level at 1 and 2 h post-irradiation. Experiments using semi-quantitative RT-PCR demonstrate that UVA increased the half-life of the COX-2 message by more than fourfold in the presence of Actinomycin D (with a half life between 4 and 8 h post-irradiation), suggesting that UVA induction of COX-2 is post-transcriptionally regulated.

UVA irradiation-induced activation of activator protein-1 is correlated with induced expression of AP-1 family members in the human keratinocyte cell line HaCaT.

To determine whether the transcription factor activator protein-1 (AP-1) could be modulated by ultraviolet A (UVA) exposure, we examined AP-1 DNA-binding activity and transactivation after exposure to UVA in the human immortalized keratinocyte cell line HaCaT. Maximal AP-1 transactivation was observed with 250 kJ/m2 UVA between 3 and 4 h after irradiation. DNA binding of AP-1 to the target 12-O-tetradecanoylphorbol-13-acetate response element sequence was maximally induced 1-3 h after irradiation.