The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression.

The heterogeneous nuclear ribonucleoproteins (hnRNP) are a family of proteins which share common structural domains, and extensive research has shown that they have central roles in DNA repair, telomere biogenesis, cell signaling and in regulating gene expression at both transcriptional and translational levels. Through these key cellular functions, individual hnRNPs have a variety of potential roles in tumour development and progression including the inhibition of apoptosis, angiogenesis and cell invasion. The aims of this review are to provide an overview of the multi functional roles of the hnRNPs, and how such roles implicate this family as regulators of tumour development. The different stages of tumour development that are potentially regulated by the hnRNPs along with their aberrant expression profiles in tumour tissues will also be discussed.

Cytochrome p450 profile of colorectal cancer: identification of markers of prognosis.

PURPOSE: The cytochromes P450 (P450) are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs, carcinogens, and endogenous compounds. The purpose of this study was to define the P450 profile of colorectal cancer and establish the prognostic significance of expression of individual P450s in colorectal cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 P450s was done on a colorectal cancer tissue microarray consisting of 264 primary colorectal cancers, 91 lymph node metastasis, and 10 normal colorectal samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: The most frequently expressed form of P450 in normal colon was CYP3A4. In primary colorectal cancer, several P450s (CYP1B1, CYP2S1, CYP2U1, CYP3A5, and CYP51) were present at a significantly higher level of intensity compared with normal colon. P450 expression was also detected in lymph node metastasis and the presence of several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP4V2, and CYP39) in the lymph node metastasis strongly correlated with their presence in corresponding primary tumors. The presence of strong CYP51 (log-rank = 12.11, P = 0.0005) or strong CYP2S1 (log-rank = 6.72, P = 0.0095) immunoreactivity were associated with poor prognosis. CYP51 was also an independent marker of prognosis (P = 0.009). CONCLUSIONS: The expression of individual P450s has been established in colorectal cancer. Several P450s show increased expression in colorectal cancer. High expression of CYP51 or CYP2S1 were associated with poor prognosis and CYP51 is an independent marker of prognosis.

Profiling cytochrome P450 expression in ovarian cancer: identification of prognostic markers.

PURPOSE: The cytochromes P450 are a multigene family of enzymes with a central role in the oxidative metabolism of a wide range of xenobiotics, including anticancer drugs and biologically active endogenous compounds. The purpose of this study was to define the cytochrome P450 profile of ovarian cancer and identify novel therapeutic targets and establish the prognostic significance of expression of individual cytochrome P450s in this type of cancer. EXPERIMENTAL DESIGN: Immunohistochemistry for a panel of 23 cytochrome P450s and cytochrome P450 reductase was done on an ovarian cancer tissue microarray consisting of 99 primary epithelial ovarian cancers, 22 peritoneal metastasis, and 13 normal ovarian samples. The intensity of immunoreactivity in each sample was established by light microscopy. RESULTS: In primary ovarian cancer, several P450s (CYP1B1, CYP2A/2B, CYP2F1, CYP2R1, CYP2U1, CYP3A5, CYP3A7, CYP3A43, CYP4Z1, CYP26A1, and CYP51) were present at a significantly higher level of intensity compared with normal ovary. P450 expression was also detected in ovarian cancer metastasis and CYP2S1 and P450 reductase both showed significantly increased expression in metastasis compared with primary ovarian cancer. The presence of low/negative CYP2A/2B (log rank = 7.06, P = 0.008) or positive CYP4Z1 (log rank = 6.19, P = 0.01) immunoreactivity in primary ovarian cancer were each associated with poor prognosis. Both CYP2A/2B and CYP4Z1 were also independent markers of prognosis. CONCLUSIONS: The expression profile of individual P450s has been established in ovarian cancer. Several P450s show increased expression in ovarian cancer and this provides the basis for developing P450-based therapeutics in ovarian cancer. Expression of CYP2A/2B or CYP4Z1 in primary ovarian cancer were independent markers of prognosis.

Cytochrome P450 enzymes: novel options for cancer therapeutics.

The concept of overexpression of individual forms of cytochrome P450 enzymes in tumor cells is now becoming well recognized. Indeed, a growing body of research highlights the overexpression of P450s, particularly CYP1B1, in tumor cells as representing novel targets for anticancer therapy. The purpose of this review is to outline the novel therapeutic options and opportunities arising from both enhanced endogenous expression of cytochrome P450 in tumors and cytochrome P450-mediated gene therapy.

Quantitative analysis of the Ah receptor/cytochrome P450 CYP1B1/CYP1A1 signalling pathway.

Cytochrome P450 (CYP) drug metabolising enzymes CYP1A1 and CYP1B1 are regulated through the ligand-activated aryl hydrocarbon (Ah) receptor. Differential expression of CYP1A1 and CYP1B1 mRNA and protein has previously been reported in human tissues with the presence of the message often extrapolated to indicate the presence of protein. The aim of this study was to clarify these potentially misleading findings, by analysing components of the Ah receptor pathway (CYP1B1, CYP1A1, Ah receptor and ARNT) using a combination of quantitative real-time RT-PCR and immunoblotting. Three human cell lines (MOG-G-CCM, MCF7 and HEPG2) known to differentially express CYP1A1 and CYP1B1 mRNA and protein were exposed to the Ah receptor agonist 3-MC, and basal and inducible levels of CYP1A1, CYP1B1, Ah receptor and ARNT were determined. The key finding of this study was the demonstration of equivalent levels of CYP1B1 mRNA in both the treated and untreated MOG-G-CCM cell lines, with expression of the corresponding CYP1B1 protein only after exposure to an Ah receptor agonist. This finding suggests that a post-transcriptional mechanism is involved in the regulation of CYP1B1. In addition, the expression pattern of CYP1B1 mRNA and protein in the MOG-G-CCM cells highlights this cell line as a potential model for studying CYP1B1 expression in human tissue.