Identification and validation of PCDHGA12 and PRRX1 methylation for detecting lung cancer in bronchial washing sample
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PROVIDER: PRJNA1033541 | ENA |
REPOSITORIES: ENA
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Project description:Bronchoscopy is a frequently used initial diagnostic procedure for patients with suspected lung cancer (LC). Cytological examinations of bronchial washing (BW) samples obtained during bronchoscopy often yield inconclusive results regarding LC diagnosis. The present study aimed to identify molecular biomarkers as a non-invasive method for LC diagnosis. Aberrant DNA methylation is used as a useful biomarker for LC. Therefore, microarray-based methylation profiling analyses on 13 patient-matched tumor tissues at stages I-III vs. non-tumor tissues were performed, and a group of highly differentially methylated genes was identified. A subsequent analysis using bisulfite-pyrosequencing with additional tissues and cell lines revealed six methylated genes [ADAM metallopeptidase with thrombospondin type 1 motif 20, forkhead box C2 (mesenchyme forkhead 1), NK2 transcription factor related, locus 5 (Drosophila), oligodendrocyte transcription factor 3, protocadherin γ subfamily A 12 (PCDHGA12) and paired related homeobox 1 (PRRX1)] associated with LC. Next, a highly sensitive and accurate detection method, linear target enrichment-quantitative methylation-specific PCR in a single closed tube, was applied for clinical validation using BW samples from patients with LC (n=68) and individuals with benign diseases (n=33). PCDHGA12 and PRRX1 methylation were identified as the best-performing biomarkers to detect LC. The two-marker combination showed a sensitivity of 82.4% and a specificity of 87.9%, with an area under the curve of 0.891. Notably, the sensitivity for small cell LC was 100%. The two-marker combination had a positive predictive value of 93.3% and a negative predictive value of 70.7%. The sensitivity was higher than that of cytology, which only had a sensitivity of 50%. The methylation status of the two-marker combination showed no association with sex, age or stage, but was associated with tumor location and histology. In conclusion, the present study showed that the regulatory regions of PCDHGA12 and PRRX1 are highly methylated in LC and can be used to detect LC in BW specimens as a diagnostic adjunct to cytology in clinical practice.
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Project description:Post-hybridization washing is an essential part of microarray experiments. Both, the quality of the experimental washing protocol and the adequate consideration of washing in intensity calibration ultimately affect the quality of the expression estimates extracted from the microarray intensities. We conducted experiments on GeneChip microarrays with altered protocols for washing, scanning and staining to study the probe-level intensity changes as a function of washing cycles. Particularly, three Affymetrix GeneChip HGU133plus2 arrays were hybridized and equilibrated for 16 hours in the hybridization oven. For one of the three arrays washing and staining was performed according to the manufacturer’s instructions. For another array the first scan was done immediately after low stringent wash and staining without intermitting stringent washing. Then, the array was stringently washed and scanned in alternating order three more times where each washing step consists of a definite number of washing cycles. The third array was low stringently washed followed by two stringent washing cycles and staining before the first scan. Subsequently it was analogously processed as array A. All three chips are repeatedly processed in a second series of alternating wash/scan-cycles which was performed using the same protocol for each chip as in the first series as described above. As in the first series the arrays were also stained a second time to compensate for any loss of bleached fluorescent dye. Analysis of the washing kinetics shows that the signal-to-noise ratio doubles roughly every ten stringent washing cycles. Washing can be characterized by time-dependent rate constants which reflect the heterogeneous character of target binding to microarray probes. We propose an empirical washing function which estimates the survival of probe bound targets. The washing function allows calibrating probe intensities for the effect of washing. On a relative scale, proper calibration for washing markedly increases expression measures especially in the limit of small and large values.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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Project description:Although cancer associated fibroblasts (CAF) play a critical role in cancer progression, their identities are still unknown. Because cells’ own identity is determined by core regulatory circuit (CRC) comprising master transcription factors (TFs), it is critical to find CAF’s master TF. Therefore, we attempt to find master TF of CAF through the extensive screening of single cell RNA-seq database of cancer tissues, and discovered Prrx1, master regulator of embryonic mesenchymal cells, as candidate for master TF of CAF. Prrx1 was abundantly expressed in CAFs with significant correlation with unfavorable clinical outcomes. Furthermore, Prrx1 in fibroblasts dramatically enhanced tumor progression and metastasis in fibroblast-specific Prrx1 inducible mice. On the other hand, tumor formation was severely inhibited in conditional Prrx1 knock-down mice. Finally, we confirmed that Prrx1 is a master TF of CAF and normal fibroblast executing wound healing program using ChIP-SEQ, CRC modeling, and in vivo validation. Furthermore we also revealed that targeting Prrx1 in fibroblast alone induced complete remission of chemotherapy-resistant cancer in preclinical mouse experiments.
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