👤 Michael Abend

A strong, consistent association between childhood irradiation and subsequent thyroid cancer provides an excellent model for studying radiation carcinogenesis. We evaluated gene expression in 63 paired RNA specimens from frozen normal and tumour thyroid tissues with individual iodine-131 (I-131) doses (0.008-8.6 Gy, no unirradiated controls) received from Chernobyl fallout during childhood (Ukrainian-American cohort). Approximately half of these randomly selected samples (32 tumour/normal tissue RNA specimens) were hybridised on 64 whole-genome microarrays (Agilent, 4 × 44 K). Associations between I-131 dose and gene expression were assessed separately in normal and tumour tissues using Kruskal-Wallis and linear trend tests. Of 155 genes significantly associated with I-131 after Bonferroni correction and with ≥2-fold increase per dose category, we selected 95 genes. On the remaining 31 RNA samples these genes were used for validation purposes using qRT-PCR. Expression of eight genes (ABCC3, C1orf9, C6orf62, FGFR1OP2, HEY2, NDOR1, STAT3, and UCP3) in normal tissue and six genes (ANKRD46, CD47, HNRNPH1, NDOR1, SCEL, and SERPINA1) in tumour tissue was significantly associated with I-131. PANTHER/DAVID pathway analyses demonstrated significant over-representation of genes coding for nucleic acid binding in normal and tumour tissues, and for p53, EGF, and FGF signalling pathways in tumour tissue. The multistep process of radiation carcinogenesis begins in histologically normal thyroid tissue and may involve dose-dependent gene expression changes. Show less

Immunoconjugates composed of the alpha-emitter (213)Bi and the monoclonal antibody d9MAb specifically target HSC45-M2 gastric cancer cells expressing mutant d9-E-cadherin. These conjugates efficiently killed tumor cells in a nude mouse peritoneal carcinomatosis model. To elucidate the molecular responses of HSC45-M2 cells to alpha-emitter irradiation, whole genome gene expression profiling was performed. For that purpose HSC45-M2 cells were incubated with lethal doses of (213)Bi-d9MAb. RNA was isolated at 6, 24 and 48 h after irradiation, transcribed into cDNA and hybridized to whole genome microarrays. Results of microarray analysis were validated using RTQ-PCR showing correspondence of approximately 90%. Following incubation with (213)Bi-d9MAb, 682-1125 genes showed upregulation and 666-1278 genes showed downregulation at one time point, each. Eight genes appeared upregulated and 12 genes downregulated throughout. Molecular functions and biological processes of differentially expressed genes were categorized according to the PANTHER database. Following (213)Bi-d9MAb irradiation also a time-dependent shift in terms of overrepresentation of biological processes was observed. Among the genes showing continuous upregulation, COL4A2, NEDD9 and C3 have not been associated with the cellular response to high LET radiation so far. The same holds true for WWP2, RFX3, HIST4H4 and JADE1 that showed continuous downregulation. According to PANTHER, three of the consistently upregulated (ITM2C, FLJ11000, MSMB) and downregulated (HCG9, GAS2L3, FLJ21439) genes, respectively, have not been associated with any biological process or molecular function so far. Thus, these findings revealed interesting new targets for selective elimination of tumor cells and new insights regarding response of tumor cells to alpha-emitter exposure. Show less