Recombinant Human PCSK2 (aa 110-638)[His]

Thyroid nodules are common. It would very helpful if genetic markers that can diagnose malignancy from fine needle aspiration samples were available. Few such markers has been thus identified and none are specific. Large panels of potential markers can be screened by microarray technology. Studies done to date have concentrated on single tumor types and thus provide no help in identifying tumor subtype specific markers. To that end we have studied gene profiles of 5 types of benign and malignant thyroid nodular tissue ( multinodular goiter, follicular adenoma, papillary and follicular carcinomas). We have identified 195 genes whose differential expression clustered into clinically relevant groups. Twenty-eight genes were selected for further confirmation using real time quantitative polymerase chain reaction. Despite the differences in the microarray panels used, we confirmed the differential regulation of 12 genes previously reported in thyroid cancer, although we found the expression of several genes to be regulated in other histological tumor subtypes than originally described. We found, PCSK2, TRIB1, RAP1 GA1 to be specifically overexpressed in follicular cancer and S100A4 and GK2 in papillary carcinoma. SERP1, RNASE2 and STATA5 were suppressed in papillary thyroid cancer. We have thus identified new potential markers specific to malignant thyroid tumors. It is apparent that a range of nodular thyroid tissue using large tumor sample numbers is necessary to establish robust markers for malignancy and to categorize tumors on the basis of small tumor samples.

Genome-wide association studies have revealed > 60 loci associated with type 2 diabetes ( T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.