Regulation of Epidermal Growth Factor Receptor Signaling and Erlotinib Sensitivity in Head and Neck Cancer Cells by miR-7

Elevated expression and activity of the epidermal growth factor receptor (EGFR)/protein kinase B (Akt) signaling pathway is associated with development, progression and treatment resistance of head and neck cancer (HNC). Several studies have demonstrated that microRNA-7 (miR-7) regulates EGFR expression and Akt activity in a range of cancer cell types via its specific interaction with the EGFR mRNA 3′-untranslated region (3′-UTR). In the present study, we found that miR-7 regulated EGFR expression and Akt activity in HNC cell lines, and that this was associated with reduced growth in vitro and in vivo of cells (HN5) that were sensitive to the EGFR tyrosine kinase inhibitor (TKI) erlotinib (Tarceva). miR-7 acted synergistically with erlotinib to inhibit growth of erlotinib-resistant FaDu cells, an effect associated with increased inhibition of Akt activity. Microarray analysis of HN5 and FaDu cell lines transfected with miR-7 identified a common set of downregulated miR-7 target genes, providing insight into the tumor suppressor function of miR-7. Furthermore, we identified several target miR-7 mRNAs with a putative role in the sensitization of FaDu cells to erlotinib. Together, these data support the coordinate regulation of Akt signaling by miR-7 in HNC cells and suggest the therapeutic potential of miR-7 alone or in combination with EGFR TKIs in this disease.     

Morphological variation and heritability in three Melanesian populations: A multivariate approach

In two previous papers Giles, Walsh and Bradley ('66) and Giles, Wyber and Walsh ('70) have shown that the inhabitants of three adjacent villages on the edge of the Markham Valley in New Guinea have significant heterogeneity in all blood group frequencies tested. The language, environment, culture, and ancestry of these people are essentially identical. The differences in the blood group frequencies were attributed to genetic drift and particularly to founder effect. In this paper the anthropometric data from these villages are analysed. Analysis of variance shows that 50% of the traits are significantly different. Multiple discriminant analysis demonstrates that the villages can be significantly separated morphologically. The heritability of each trait is determined using an analysis of within and among sibship variation. Traits with strong “genetic” components of variation and traits with strong “environmental” components contribute significantly to the morphological heterogeneity among the villages. Some speculations are presented on the cause of the “genetic” component of morphological variation.     

Germline HOXB13 p.Gly84Glu mutation and risk of colorectal cancer

Introduction: The HOXB13 pGly84Glu mutation has recently been associated with an increased risk of prostate cancer but the association of other cancer sites with this allele has not been assessed. Data has suggested that HOXB13 expression levels are decreased in colorectal cancer (CRC) cell lines indicating this gene may be involved in colorectal tumourigenesis. Methods: To evaluate a potential association of this mutation with CRC, we genotyped the mutation in 2695 CRC cases and 4593 controls from population-based registries in Canada and Australia. Results: The HOXB13 pGly84Glu mutation was more common in CRC cases than controls (0.48% vs. 0.17%, P = 0.02) indicating a significant association between the HOXB13 variant and CRC risk (OR = 2.8; 95%CI: 1.2–6.8). This association was attenuated but remained significant with the inclusion of previously published and publicly available genotype data. Pedigree analysis of cases and controls revealed that 7/21 HOXB13 mutation carriers had a family history of prostate cancer. Discussion: This report is the first to suggest a risk of CRC associated with mutations in the HOXB13 gene. These findings require further validation but may be of importance in the screening and genetic counseling of families known to carry the HOXB13 pGly84Glu mutation.     

On the chemical basis of chromosome banding patterns.

A comparative study of the staining characteristics of four reagents for human chromosomes has been carried out. The four reagents are: (I) quinacrine mustard, as an alkylating agent, (II) the dihydroxy derivative of quinacrine mustard, (III) quinacrine, and (IV) 9-amino-6-chloro-2-methoxyacridine. The last reagent does not possess the amino substituted side chain even though it has the same intercalating nucleus. Comparison of the first three compounds in their staining and banding behavior suggested the initial step leading to banding may be the displacement of the nucleoprotein sites in hcromosomes. The Q and G banding could be blocked experimentally by treating the chromosome preparation with dimethylamine solution. This result may suggest that these sites have weaker basic proteins (nonhistone proteins?). The use of compound IV, which does not have the side chain in the molecule but does have the same intercalating chromophore, did not lead to banding and gives indirect support to this hypothesis. A combined use of compound IV and quinacrine may be useful for the determination of total DNA vs. banding DNA.     

An epitope on C4 β light (L) chains detected by human anti-Rg; its relationship with β chain polymorphism and MHC associations

Two out of ten Rg-specific antisera tested contain a third antibody specific for the β chain of C4. Analysis of the β chains of 66 unrelated individuals by sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed that the epitope detected is located exclusively on the light (L) β chain. A strong, but incomplete, association between the β chain epitope and the expression of the Rg: 2 determinant on the α chain of the same protein was also observed. While H (heavy) and L β chains were not associated with a particular C4 isotype, previously unrecorded associations of β chain polymorphism with theDR locus have been established.     

Distribution of β-thalassemia trait and erythrocyte glucose-6-phosphate dehydrogenase deficiency in the Markham river valley of New Guinea

Ten villages in or near the Markham Valley, northeastern New Guinea, have provided a sample of 476 males for the ascertainment of glucose-6-phosphate dehydrogenase (G6PD) deficiency and 810 individuals of both sexes for the investigation of the β-thalassemia trait. An extreme heterogeneity was found in the prevalence of both traits when the villages were analyzed separately (from 1.5% to 18.2% demonstrating G6PD deficiency and from 0 to 22.8% evincing β-thalassemia trait). The latter result counters an earlier report from the same region that β-thalassemia trait frequencies correlated negatively with altitude and (presumably) positively with endemicity of malaria. The present findings, based on a more representative sample, do not necessarily invalidate the relationship between malaria and β-thalassemia trait suggested by earlier studies, but they do make clear that correlation in New Guinea, at least, may be complicated by random genetic drift, although other possibilities are discussed. The heterogeneous distribution of G6PD deficiency in the present study confirms similar earlier findings. The importance of sample provenience and anthropological data in the interpretation of differences in the distribution of genetically determined traits is stressed.