The cell cycle and mitosis caused by HPV in vitro [59,75,76] and

The cell cycle and mitosis caused by HPV in vitro [59,75,76] and correlated in few CC studied [59]. The E6 and E7 oncoproteins of high-risk HPVs induce numerous mitotic defects, including multipolar mitoses, chromosomal missegregation, anaphase bridges, and aneuploidy. Although cells with abnormal mitoses are normally targeted for cell death, E6 and E7 act cooperatively to allow cells with abnormal centrosomes to accumulate by relaxing the G2/M checkpoint response and inhibition of MedChemExpress Indacaterol (maleate) Iloperidone metabolite Hydroxy Iloperidone web apoptotic signaling [76]. In agreement with these data, the canonical pathways of G2/M DNA Damage Checkpoint Regulation and the Role of CHK Proteins in Cell Cycle Checkpoint Control ranked at the second and fifth positions of the altered canonical pathways in CC. On the other hand, E6 and E7 induce mechanisms to avoid mitosis checkpoint. The E6/E7 genes have been shown to induce the overexpression of CDC20 and UBCH10, which activate the APC/C ubiquitin ligase complex [55]. The enrichment of positive regulation of ubiquitin-protein ligase activity during mitotic cell cycle found in CCs (Table 5) completely agree with these in vitro results. Inhibition of mitosis is a well-known strategy to combat cancers. Drugs that perturb the process of cell division have proved to be effective anticancer therapies. Well-known examples of these drugs are those that perturb the formation of the mitotic spindle, such as taxanes and vinca alkaloids. However, they have remarkably low therapeutic indices and narrow therapeutic windows. Their efficacy is restricted because they also perturb the microtubule network of non-dividing cells, causing neurotoxic effects and affecting endothelial cell function. To resolve this issue, a new generation of antimitotic agents has been developed that target kinesins and kinases with unique roles in mitosis, such as KIF11, PLK1, and aurora kinase A (AURKA) [69]. Interestingly, the transcripts of these 3 genes were also upregulated in the CCs (Table S3), AURKA ranked in 19th place, KIF11 ranked in 72ndplace, and PLK1 ranked in 263rd place. Therefore, those drugs could be tested for the treatment of cervical cancer. On the other hand, the high FC of the novel genes validated in this work, especially CDKN3, CDC20, and SYCP2, compared with the control samples, makes these genes potential targets for CC therapy. However, it is still necessary to demonstrate whether they are indispensable for tumor growth.Supporting InformationFigure S1 Correlation of expression intensity of 997 genes examined by HG-Focus and HG-ST1.0 microarrays. The Log2 values of the standardized intensity signals (RMA values) of 997 genes in a typical tumor (R230) examined by the 2 microarrays were plotted. The linear trend (black line) is included, which was calculated with Person’s correlation test: r = 0.78, p,1610215. (TIF) Figure S2 Validation of gene expression of 3 genetic markers by qRT-PCR. The intensity of gene expression, expressed in Log2 values, is shown in box plots. Expression of the 3 novel downregulated genes revealed in this study (CFD, EDN3, WISP2) associated with CC are compared between healthy cervical epitheliums (Control, n = 25) and invasive CC (Tumor, n = 44). See legend of Figure 4. (TIF) Figure S3 Histological analysis of NUSAP1. Protein expression was determined by immunohistochemistry using sections from formalin-fixed, paraffin-embedded tissue. Representative experiments 1407003 in adeno cell carcinomas (left panel) and squamous cell carcinomas (right panel.The cell cycle and mitosis caused by HPV in vitro [59,75,76] and correlated in few CC studied [59]. The E6 and E7 oncoproteins of high-risk HPVs induce numerous mitotic defects, including multipolar mitoses, chromosomal missegregation, anaphase bridges, and aneuploidy. Although cells with abnormal mitoses are normally targeted for cell death, E6 and E7 act cooperatively to allow cells with abnormal centrosomes to accumulate by relaxing the G2/M checkpoint response and inhibition of apoptotic signaling [76]. In agreement with these data, the canonical pathways of G2/M DNA Damage Checkpoint Regulation and the Role of CHK Proteins in Cell Cycle Checkpoint Control ranked at the second and fifth positions of the altered canonical pathways in CC. On the other hand, E6 and E7 induce mechanisms to avoid mitosis checkpoint. The E6/E7 genes have been shown to induce the overexpression of CDC20 and UBCH10, which activate the APC/C ubiquitin ligase complex [55]. The enrichment of positive regulation of ubiquitin-protein ligase activity during mitotic cell cycle found in CCs (Table 5) completely agree with these in vitro results. Inhibition of mitosis is a well-known strategy to combat cancers. Drugs that perturb the process of cell division have proved to be effective anticancer therapies. Well-known examples of these drugs are those that perturb the formation of the mitotic spindle, such as taxanes and vinca alkaloids. However, they have remarkably low therapeutic indices and narrow therapeutic windows. Their efficacy is restricted because they also perturb the microtubule network of non-dividing cells, causing neurotoxic effects and affecting endothelial cell function. To resolve this issue, a new generation of antimitotic agents has been developed that target kinesins and kinases with unique roles in mitosis, such as KIF11, PLK1, and aurora kinase A (AURKA) [69]. Interestingly, the transcripts of these 3 genes were also upregulated in the CCs (Table S3), AURKA ranked in 19th place, KIF11 ranked in 72ndplace, and PLK1 ranked in 263rd place. Therefore, those drugs could be tested for the treatment of cervical cancer. On the other hand, the high FC of the novel genes validated in this work, especially CDKN3, CDC20, and SYCP2, compared with the control samples, makes these genes potential targets for CC therapy. However, it is still necessary to demonstrate whether they are indispensable for tumor growth.Supporting InformationFigure S1 Correlation of expression intensity of 997 genes examined by HG-Focus and HG-ST1.0 microarrays. The Log2 values of the standardized intensity signals (RMA values) of 997 genes in a typical tumor (R230) examined by the 2 microarrays were plotted. The linear trend (black line) is included, which was calculated with Person’s correlation test: r = 0.78, p,1610215. (TIF) Figure S2 Validation of gene expression of 3 genetic markers by qRT-PCR. The intensity of gene expression, expressed in Log2 values, is shown in box plots. Expression of the 3 novel downregulated genes revealed in this study (CFD, EDN3, WISP2) associated with CC are compared between healthy cervical epitheliums (Control, n = 25) and invasive CC (Tumor, n = 44). See legend of Figure 4. (TIF) Figure S3 Histological analysis of NUSAP1. Protein expression was determined by immunohistochemistry using sections from formalin-fixed, paraffin-embedded tissue. Representative experiments 1407003 in adeno cell carcinomas (left panel) and squamous cell carcinomas (right panel.

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