Potential Molecular Mechanisms for Improved Prognosis and Outcome with Neoadjuvant Chemotherapy Prior to Laparoscopical Radical Hysterectomy for Patients with Cervical Cancer

Background: The p53:miR-34a:E2F positive feed-forward loop and the p53:miR-605:Mdm2 positive feed-back loop have been identified to be crucial oncogenesis/tumor suppressor-regulating signaling pathways. In this study, we sought to examine the hypothesis that neoadjuvant chemotherapy (NAC) is a better approach with improved prognosis and outcomes after laparoscopical radical hysterectomy (LRH) on patients with cervical cancer and to elucidate the potential roles of the p53:miR-34a:E2F1 and the p53:miR-605:Mdm2 signaling pathways in this therapy. Methods: Twenty-one patients with stage IIB cervical cancer were recruited to this study and they were randomly divided into two groups: LRH (n=10) and NAC+LRH (n=11) groups. The NAC+LRH group consisted of 4 cycles of cisplatin, paclitaxel and carboplatin. Complication rates and NAC outcomes (tumor size changes, 2-year disease-free survival rate, and 2-year overall survival rate) were compared between the two groups. Expression of p53, Mdm2, E2F1, miR-34a, and miR-605 at mRNA and protein levels from the tumor tissues was analyzed. Results: We observed that the diameter of tumors following chemotherapy was substantially smaller in the NAC+LRH patients than in LRH patients. No recurrence or metastasis after surgery was observed in the NAC+LRH patients, whereas 2 out of 10 LRH patients had recurrences and 1 had metastasis. The 2-year disease-free and overall survival rates were apparently higher in the NAC+LRH group than in the LRH group. Furthermore, molecular biology analyses revealed that the protein and mRNA levels of p53 were both markedly increased in patients who received NAC than those who did not, and oppositely, the levels of E2F1 and Mdm2 were significantly lower in the NAC+LRH patients than in the LRH patients. The levels of miR-34a and miR-605 were considerably higher with NAC relative to without NAC. Among the three anti-cancer drugs included in NAC, cisplatin was found to be the main component that caused increases in p53 protein levels, miR-34a and miR-605 miRNA levels, and decreases in Mdm2 and E2F1 protein levels. Furthermore, ERK1/2 inhibitor U0126 or TAB1 siRNA mitigated these changes induced by cisplatin. Conclusion: These findings not only indicate NAC as a rational approach for better treatment of cervical cancer with improved therapeutic outcomes, due partly to the ability of cisplatin to promote the p53:miR-34a:E2F1 positive feed-forward loop and the p53:miR-605:Mdm2 positive feedback loop.