Differential Transcriptome Profile of Peripheral White  Cells to Identify Biomarkers Involved in Oxaliplatin  Induced Neuropathy

Morales, Manuel; Ávila, Julio; González-Fernández, Rebeca; Boronat, Laia; Soriano, M L; Martín‐Vasallo, Pablo

doi:10.3390/jpm4020282

Cited by 9 publications

(15 citation statements)

References 61 publications

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“…Previous research from our group has led to the identification of several genes, which were shown to be significantly up-, or down- regulated in peripheral white cells (PWCs) of CRC patients, due to oxaliplatin-based chemotherapy (Morales et al, 2014 ). Interestingly, one of the differentially expressed genes was the isoform α3 of the Na,K-ATPase ; mRNA levels of Na,K-ATPase α3 subunit were down-regulated 2.6-fold.…”

Section: Introductionmentioning

confidence: 99%

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

et al. 2016

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The goal of this study was to define Na,K-ATPase α and β subunit isoform expression and isozyme composition in colorectal cancer cells and liver metastases. The α1, α3, and β1 isoforms were the most highly expressed in tumor cells and metastases; in the plasma membrane of non-neoplastic cells and mainly in a cytoplasmic location in tumor cells. α1β1 and α3β1 isozymes found in tumor and metastatic cells exhibit the highest and lowest Na+ affinity respectively and the highest K+ affinity. Mesenchymal cell isozymes possess an intermediate Na+ affinity and a low K+ affinity. In cancer, these ions are likely to favor optimal conditions for the function of nuclear enzymes involved in mitosis, especially a high intra-nuclear K+ concentration. A major and striking finding of this study was that in liver, metastasized CRC cells express the α3β1 isozyme. Thus, the α3β1 isozyme could potentially serve as a novel exploratory biomarker of CRC metastatic cells in liver.

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Section: Introductionmentioning

confidence: 99%

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

et al. 2016

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“…In a previous screening for biomarkers involved in oxaliplatin toxicity, FKBP5 was the gene whose transcriptional expression level was most downregulated quantitatively ( 5 ). In the current study, IHC analysis of FKBP51 protein expression and localization allowed observation of strong staining in the nuclei of enterocytes in healthy colon, whereas in colonic adenocarcinoma cells, the staining was localized in nuclei and cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of biomarkers that could predict the onset of these secondary effects would be of great value in preventing long-term toxicity or permanent damage in patients at risk. Recent research from our laboratory has led to the identification of several genes that are significantly up- or downregulated in peripheral white cells (PWCs) of CRC patients following oxaliplatin-based chemotherapy treatment ( 5 ). In our screening, the expression levels of the gene encoding for the immunophilin FK506-binding protein 5 (FKBP51) were 2.76-times lower [3,812 (pre) vs. 1,383 (post)] in PWCs after 3 cycles of oxaliplatin-based chemotherapy ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

Expression and localization of the immunophilin FKBP51 in colorectal carcinomas and primary metastases, and alterations following oxaliplatin-based chemotherapy

et al. 2016

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The immunophilin FK506-binding protein 5 (FKBP51) is a scaffold protein that serves a pivotal role in the regulation of multiple signaling pathways, integrating external and internal stimuli into distinct signal outputs. In a previous study, we identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of colorectal adenocarcinoma (CRC) patients undergoing oxaliplatin-based chemotherapy. In our screening, FKBP51 gene expression was downregulated following chemotherapy. In order to determine whether this alteration in gene expression observed in PWCs may be detected at the protein level in tumors and metastases following the administration of adjuvant chemotherapy, an immunohistochemical analysis of FKBP51 in CRC and primary metastasis tissues was performed. The present study confirmed the downregulation of FKBP51 gene expression elicited by chemotherapy with folinic acid (leucovorin), fluorouracil and oxaliplatin in metastasized liver tissue that had been resected after the oxaliplatin-based chemotherapy, compared with tissue section samples of CRC from patients (prior to antineoplastic treatment). Furthermore, the results indicated that, in CRC tissue sections, the expression of FKBP51 protein is associated with an immature phenotype of stromal fibroblasts and with the epithelial-to-mesenchymal transition (EMT) phenotype, suggesting a role for this protein in the EMT process in CRC. Finally, the observation that only certain cells of the stroma express FKBP51 protein suggests a potential role for this immunophilin as a stroma cell subtype marker.

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“…In an attempt to identify biomarkers that may predict the onset of these secondary effects, a recent study investigated the differential gene expression of peripheral leukocytes in patients with CRC prior to and following 3 cycles of oxaliplatin-based CT ( 3 ). The study identified 502 differentially-expressed genes that were significantly up- or downregulated in the peripheral white cells (PWCs) of patients following CT treatment ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

“…To determine whether the changes in gene expression observed in PWCs may be detected in tumors following the administration of adjuvant CT, the present study performed immunohistochemical analysis of a selected number of genes that had previously been identified in the differential transcriptome profile ( 4 ). The study observed that one gene among four, whose transcriptional expression levels varied from ‘off’ to ‘on’, was that coding for IQ-motif containing GTPase activating protein 1 (IQGAP1) ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

Alterations in IQGAP1 expression and localization in colorectal carcinoma and liver metastases following oxaliplatin-based chemotherapy

et al. 2017

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IQGAP1 is a scaffolding protein that serves a key role in cell dynamics by integrating internal and external stimuli to distinct signal outputs. Previous studies have identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of patients with colorectal adenocarcinoma (CRC), who underwent oxaliplatin-based chemotherapy (CT). In addition, screening studies have reported that IQ-motif containing GTPase activating protein 1 (IQGAP1) transcriptional expression levels varied from ‘off’ to ‘on’ following oxaliplatin CT. In order to determine if variations previously described in PWCs are able to be observed at the protein level in tumors and in metastases following CT, the present study performed an immunohistochemical analysis of IQGAP1 in CRC and primary metastases. IQGAP1 expression was observed in the nuclear envelope and in lateral cell membranes and cytoplasm in normal colon tissue. However, in tumor tissue, cells exhibited a diffuse pattern, with variable expression levels of staining in the nuclear membrane and cytoplasm, with the highest expression intensity observed at the invasive front. In healthy and metastasized liver tissue and in the metastases themselves, expression levels varied from cell to cell from no expression to a high level. In the majority of cells, IQGAP1 co-localized with microtubules at the cytoplasmic face of the nuclear envelope. Strong positive expression was observed in areas of the lesion where cells were detaching from the lesion into the lumen. Despite the homogeneous IQGAP1 staining pattern observed in healthy colon tissue sections, CRC demonstrated heterogeneity in staining, which was more marked in metastasized liver tissue resected following CT. However, the most notable findings were the observed effects on the cellular and subcellular distribution and its implications for cancer biology. These results suggest that IQGAP1 may be a putative biomarker, a candidate for clinical diagnostics and a potential novel target for anti-cancer therapeutics.

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Differential Transcriptome Profile of Peripheral White Cells to Identify Biomarkers Involved in Oxaliplatin Induced Neuropathy

Cited by 9 publications

References 61 publications

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

Na,K-ATPase Isozymes in Colorectal Cancer and Liver Metastases

Expression and localization of the immunophilin FKBP51 in colorectal carcinomas and primary metastases, and alterations following oxaliplatin-based chemotherapy

Alterations in IQGAP1 expression and localization in colorectal carcinoma and liver metastases following oxaliplatin-based chemotherapy

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