Inflammation suppressor genes: please switch out all the lights

An effective immune system requires rapid and appropriate activation of inflammatory mechanisms but equally rapid and effective resolution of the inflammatory state. A review of the canonical host response to gram-negative bacteria, the lipopolysaccharide-Toll-like receptor 4 signaling cascade, highlights the induction of repressors that act at each step of the activation process. These inflammation suppressor genes are characterized by their induction in response to pathogen, typically late in the macrophage activation program, and include an expanding class of dominant-negative proteins derived from alternate splicing of common signaling components. Despite the expanse of anti-inflammatory mechanisms available to an activated macrophage, the frailty of this system is apparent in the large numbers of genes implicated in chronic inflammatory diseases. This apparent lack of redundancy between inflammation suppressor genes is discussed with regard to evolutionary benefits in generating a heterogeneous population of immune cells and consequential robustness in defense against new and evolving pathogens.

HLS5, a novel RBCC (ring finger, B box, coiled-coil) family member isolated from a hemopoietic lineage switch, is a candidate tumor suppressor

Hemopoietic cells, apparently committed to one lineage, can be reprogrammed to display the phenotype of another lineage. The J2E erythroleukemic cell line has on rare occasions developed the features of monocytic cells. Subtractive hybridization was used in an attempt to identify genes that were up-regulated during this erythroid to myeloid transition. We report here on the isolation of hemopoietic lineage switch 5 (Hls5), a gene expressed by the monocytoid variant cells, but not the parental J2E cells. Hls5 is a novel member of the RBCC (Ring finger, B box, coiled-coil) family of genes, which includes Pml, Herf1, Tif-1alpha, and Rfp. Hls5 was expressed in a wide range of adult tissues; however, at different stages during embryogenesis, Hls5 was detected in the branchial arches, spinal cord, dorsal root ganglia, limb buds, and brain. The protein was present in cytoplasmic granules and punctate nuclear bodies. Isolation of the human cDNA and genomic DNA revealed that the gene was located on chromosome 8p21, a region implicated in numerous leukemias and solid tumors. Enforced expression of Hls5 in HeLa cells inhibited cell growth, clonogenicity, and tumorigenicity. It is conceivable that HLS5 is one of the tumor suppressor genes thought to reside at the 8p21 locus.

Novel markers for poor prognosis in head and neck cancer

Head and neck cancer (HNSCC) is one of the most distressing human cancers, causing pain and affecting the basic survival functions of breathing and swallowing. Mortality rates have not changed despite recent advances in radiotherapy and surgical treatment. We have compared the expression of over 13,000 unique genes in 7 cases of matched HNSCC and normal oral mucosa. Of the 1,260 genes that showed statistically significant differences in expression between normal and tumor tissue at the mRNA level, the three top ranking of the top 5% were selected for further analysis by immunohistochemistry on paraffin sections,. along with the tumor suppressor genes p16 and p53, in a total of 62 patients including 55 for whom >4-year clinical data was available. Using univariate and multivariate survival analysis, we identified SPARC/osteonectin as a powerful independent prognostic marker for short disease-free interval (DFI) (p < 0.002) and poor overall survival (OS) (p = 0.018) of HNSCC patients. In combination with other ECM proteins found in our analysis, PAI-1 and uPA, the association with DFI and OS became even more significant (p < 0.001). Our study represents the first instance of SPARC as an independent prognostic marker in HNSCC.

Expression and methylation pattern of TSLC1 cascade genes in lung carcinomas

TSLC1 (tumor suppressor in lung cancer-1, IGSF4) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell-cell adhesion. TSLC1 is connected to the actin cytoskeleton by DAL-1 (differentially expressed in adenocarcinoma of the lung-1, EPB41L3) and it directly associates with MPP3, one of the human homologues of a Drosophila tumor suppressor gene, Discs large. Recent data suggest that aberrant promoter methylation is important for TSLC1 inactivation in lung carcinomas. However, little is known about the other two genes in this cascade, DAL-1 and MPP3. Thus, we investigated the expression and methylation patterns of these genes in lung cancer cell lines, primary lung carcinomas and nonmalignant lung tissue samples. By reverse transcription-polymerase chain reaction, loss of TSLC1 expression was observed in seven of 16 (44%) non-small-cell lung cancer (NSCLC) cell lines and in one of 11 (9%) small-cell lung cancer (SCLC) cell lines, while loss of DAL- 1 expression was seen in 14 of 16 (87%) NSCLC cell lines and in four of 11 (36%) SCLC cell lines. By contrast, MPP3 expression was found in all tumor cell lines analysed. Similar results were obtained by microarray analysis. TSLC1 methylation was seen in 13 of 39 (33%) NSC LC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs. DAL-1 methylation was observed in 17 of 39 (44%) NSCLC cell lines, in three of 11 (27%) SCLC cell lines and in 147 of 268 (55%) primary NSCLCs. In tumors of NSCLC patients with stage II-III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease. A significant correlation between loss of expression and methylation of the genes in lung cancer cell lines was found. Overall, 65% of primary NSCLCs had either TSLC1 or DAL-1 methylated. Methylation of one of these genes was detected in 59% of NSCLC cell lines; however, in SCLC cell lines, methylation was much less frequently observed. The majority of nonmalignant lung tissue samples was not TSLC1 and DAL-1 methylated. Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2$-deoxy-cytidine. Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC.