BMC Genomics 2007, 8:117 http://www.biomedcentral.com/1471-2164/8/117 cFGeiegllnuleirnex3mproedsesilosnofcocerrveilcaatilotnisssuqeuantitatively identify better Gene expression correlations quantitatively identify better cell line models of cervical tissue. Gene expres- sion correlations were calculated for all cell lines and growth conditions against both normal cervix and cervical cancer. Cell lines were cultured in ATCC recommended media as monolayers. SiHa and HeLa cell lines were also cultured in different media as well as in an organotypic environment. In addition to the organotypic culture, a control was used that left out the fibroblasts, which prevented the epithelial cell line to stack in 3-dimensions. The primary, C4-I, and C4-II cell lines had the highest correlation to cervical cancer and therefore were the better general models of cervical cancer out of the cell lines we tested. Changing the media from MEM to DMEM increased the correlation to cervical cancer for the HeLa and SiHa cell lines, as well as culturing them in an organotypic environment. Error bars were derived from the standard deviation of the correlation of a cell line against each individual patient biopsy. had a stronger correlation (R = 0.59) for six apoptotic pathways than even the primary cell line (R = 0.56). Of even greater importance, some cell lines had negative pathway-specific correlations to cervical cancer. For exam- ple, HeLa cells cultured in monolayer had a negative (- 0.3) correlation to cervical cancer in the pathway "G-Pro- tein Signaling" (GO:7186) (Figure 4B). Fourteen out of 71 genes resulted in the negative correlation to cervical can- cer, since they showed opposite expression to cervical can- cer (>3-fold change). These genes included GNG11, CXCL1, FZD2, GNA12, CALU, GPR19, AKAP12, GRINA, 2 ESTs, CALM2, GNAI2, DGKD, and EDNRB, and had a 3– 50 fold difference when compared to cervical cancer. Researchers studying a particular gene or pathway may not be interested in the best global model if that cell line does not represent their pathway of interest. Only cell lines with the highest correlation should be used to study a specific pathway in vitro. The example where HeLa had a negative correlation to the "G-Protein Signaling" pathway is extremely important, indicating that this system is dys- regulated in these cells relative to cervical cancer. Research cVFaiangrcuiaertrieoan4tianpthatehmwoayd-eslpinegcipfiecrlfeovreml ance of cell lines to cervical Variation in the modeling performance of cell lines to cervical cancer at a pathway-specific level. A: The "Regulation of Apoptosis" pathway (GO:42981) revealed that better global model to cervical cancer (primary, C4-I, and C4-II, discussed above) were not necessarily better models of specific pathways. In this pathway, the best models among those we tested were the primary cell line and HeLa cultured in an organotypic environment. Eight genes from the sub- pathway "Anti-Apoptosis" (GO:6916) were primarily respon- sible for lowering the correlation of the C4-II cell line. An average of 71 ± 5 genes were used to calculate the correla- tion for each cell line. B: In the example of the "G-protein Signaling" pathway (GO:7186), HeLa cultured as a monolayer in ATCC recommended media had an anti-correlation (-0.3) to cervical cancer. Fourteen out of 71 genes were primarily responsible for the negative correlation to cervical cancer. An average of 72 ± 7 genes were used to calculate the corre- lation for each cell line. Page 6 of 13 (page number not for citation purposes)