The effect of preventive human papillomavirus (HPV) vaccination on the reduction of the cervical cancer (CC) burden will not be known for 30 years. Therefore, it’s still necessary to improve the procedures for CC screening and treatment. The objective of this study was to identify and characterize cellular targets that could be considered potential markers for screening or therapeutic targets. A pyramidal strategy was used. Initially the expression of 8,638 genes was compared between 43 HPV16-positive CCs and 12 healthy cervical epitheliums using microarrays. A total of 997 genes were deregulated, and 21 genes that showed the greatest deregulation were validated using qRT-PCR. The 6 most upregulated genes (CCNB2, CDC20, PRC1, SYCP2, NUSAP1, CDKN3) belong to the mitosis pathway. They were further explored in 29 low-grade cervical intraepithelial neoplasias (CIN1) and 21 high-grade CIN (CIN2/3) to investigate whether they could differentiate CC and CIN2/3 (CIN2+) from CIN1 and controls. CCNB2, PRC1, and SYCP2 were mostly associated with CC and CDC20, NUSAP1, and CDKN3 were also associated with CIN2/3. The sensitivity and specificity of CDKN3 and NUSAP1 to detect CIN2+ was approximately 90%. The proteins encoded by all 6 genes were shown upregulated in CC by immunohistochemistry. The association of these markers with survival was investigated in 42 CC patients followed up for at least 42 months. Only CDKN3 was associated with poor survival and it was independent from clinical stage (HR = 5.9, 95%CI = 1.4–23.8, p = 0.01). CDKN3 and NUSAP1 may be potential targets for the development of screening methods. Nevertheless, further studies with larger samples are needed to define the optimal sensitivity and specificity. Inhibition of mitosis is a well-known strategy to combat cancers. Therefore, CDKN3 may be not only a screening and survival marker but a potential therapeutic target in CC. However, whether it’s indispensable for tumor growth remains to be demonstrated.
The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, involved in mitosis, is upregulated in cervical cancer (CC). We investigated CDKN3 mRNA as a survival biomarker and potential therapeutic target for CC. CDKN3 mRNA was measured in 134 CC and 25 controls by quantitative PCR. A 5-year survival study was conducted in 121 of these CC patients. Furthermore, CDKN3-specific siRNAs were used to investigate whether CDKN3 is involved in proliferation, migration, and invasion in CC-derived cell lines (SiHa, CaSki, HeLa). CDKN3 mRNA was on average 6.4-fold higher in tumors than in controls (p = 8 x 10−6, Mann-Whitney). A total of 68.2% of CC patients over expressing CDKN3 gene (fold change ≥ 17) died within two years of diagnosis, independent of the clinical stage and HPV type (Hazard Ratio = 5.0, 95% CI: 2.5–10, p = 3.3 x 10−6, Cox proportional-hazards regression). In contrast, only 19.2% of the patients with lower CDKN3 expression died in the same period. In vitro inactivation of CDKN3 decreased cell proliferation on average 67%, although it had no effect on cell migration and invasion. CDKN3 mRNA may be a good survival biomarker and potential therapeutic target in CC.
CDKN3 might be useful not only as marker for survival and selection of CC patients for additional chemotherapy or specific target cancer therapy, but also as a potential target to develop specific small drugs to combat CC.
The effectiveness of a preventive human papillomavirus (HPV) vaccination for reducing the cervical cancer (CC) burden will likely not be known for 30 years. Current screening methods for detecting highgrade cervical intraepithelial neoplasias (CIN2/3) and CC (CIN2+) have low sensitivity (Pap test) or low specificity (HPV tests). Improved procedures for CC screening and treatment are therefore required. Based on comparisons with healthy cervical epithelium, the genes most upregulated and enriched in CC are those involved in mitosis. Some of these upregulated genes might be good candidates for CC screening or survival markers or as potential therapeutic targets. In this chapter, we analyze the benefits and limitations of current methods used for early CC detection, the evidence that demonstrates that the most enriched genes in CC are those involved in mitosis, the mechanism that regulates mitosis and its relationship with HPV, and our experimental evidence suggesting that some mitosis genes might be good markers for screening and survival in CC. In addition, we discuss the need to develop less expensive and more efficient methods that can be automated for large-scale application in poor and developing countries. We also discuss the potential use of the markers for other types of cancers and as potential therapeutic targets.
e17005 Background: In Mexico, cervical cancer (CaCU) is the second leading cause of death in women. New treatment strategies are now emerging specifically the pathway of PD-1. We evaluated the frequency of PD-L1 expression at mRNA level and analyzed the expression profiles associated with different levels of CD274 expression. Methods: We analyzed the mRNA of 17 controls and 59 cervical cancer tumors by an expression microarray that allows the analysis of 22,607 human genes. Tumors were classified based on the mRNA expression of CD274. The deregulated genes in each group of tumors were compared against the control group using a T-test and Fold Change value. Functional analysis was using the DAVID tool. Correlation gene analysis was performed using the Pearson test. Results: The 59 cervical cancer tumors were classified in 3 groups: CD274-, CD274 low expression and CD274 high expression. The 71.2% of the tumors of CaCU have CD274 expression, 20 tumors with low expression and 22 tumors with high expression. 786 altered genes in the CD274- group, 1759 in the group of low expression and 2465 in the group of high expression were found. We found 19 altered biological processes in the CD274- group, being the most significant, cell cycle, DNA replication and DNA repair. In the tumors CD274 low were found 20 biological processes altered and were similar to those identified in the CD274- tumors. In the group CD274 high, 28 altered biological processes were found, interestingly 5 biological processes associated with innate immune response and antigenic processing. We found 24 genes correlated with the CD274 expression related to the immune response. Conclusions: The frequency of CD274 expression in cervical cancer is similar to that found in other tumors, it would be interesting explore the correlation between mRNA and protein. The number of altered genes is higher in the group of high expression of CD274. In the CD274 high group genes associated with processes related to the immune response are altered. The genes that correlate with the expression of CD274 are mostly associated with the immune system, these results suggest that overexpression of CD274 is accompanied by other immune processes.
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