Some studies indicate that miR-143 is up-regulated in tumor tissues [10, 11]. Also, through inhibition of FNDC3B, miR-143 promotes the metastasis of hepatic carcinoma (animal study) to the lung and the metastasis of prostate cancer cells [12, 13]. However, most of the studies demonstrate that miR-143 is down-regulated in solid tumor, including esophageal cancer, bladder cancer and prostate cancer, etc. [14–16]. The target genes of miR-143 include KRAS, MACC1 and bcl-2, etc. [17–19], which are involved in the signaling pathways of ERK5 and MAPK, etc. [20, 21]. Among those target genes, bcl-2 is an oncogene involved in cell apoptosis. The function of bcl-2 protein is to inhibit apoptosis by providing cell resistance to multiple apoptosis-stimulating factors. It is reported that through targeting bcl-2, miR-181d inhibited neuroglia cell proliferation and promoted apoptosis  while miR-15b and miR-16 played a role in the drug resistance of gastric cancer .
Our results indicate that miR-143 was significantly down-regulated in cervical SCC, which was consistent with previous reports [24, 25]. They both found that miR-143 expression was down-regulated in cervical cancer cell lines and tissues. However, the relationship between miR-143 expression and clinical pathological features of cervical cancer is rarely studied. In this study, we also analyzed whether miR-143 expression was related with clinical pathological features of cervical cancer. Our results showed that the expression of miR-143 was related to the lymph node metastasis of cervical SCC. Expression of miR-143 was significantly lower in patients with lymph node metastasis than that in patients without lymph node metastasis. Similar results were found in esophageal cancer , suggesting that down-regulation of miR-143 might promote the lymph node metastasis of cancer cells. The ROC curve analysis showed that the sensitivity and specificity of miR-143 to evaluate lymph node metastasis were 75% and 60%, respectively. This data suggest that miR-143 may be used as an indicator for lymph node metastasis evaluation in clinic, especially as a reference before surgery. Moreover, our results showed that miR-143 and tumor diameter was negatively correlated. A previous study also showed that the expression of miR-143 in the colorectal cancer tissue with tumor diameter > 5 cm was lower than that with tumor diameter < 5 cm . The sensitivity and specificity of miR-143 to evaluate tumor diameter were 70.5% and 61%, respectively. The self-shedding of exogenous cervical tumor and the underdetermined tumor diameter of endogenous cervical would lower the clinical staging of tumor and influence the individualized treatment of patients. Ivanov et al. reported that in cervical cancer at stage Ib2-IIa, the lymph node metastasis rate and distant metastasis rate were increased as the tumor size enlarged , and there was certain correlation between tumor metastasis and tumor size. In addition, we found that the expression of miR-143 was irrelevant to the age, clinical stage, pathological grade and LVSI of the SCC patients.
The infection rate of high-risk HPV in cervical cancer can be up to 50%-90% . In this study, there were 60 cases (78%) of HPV positive cervical SCC patients, in which there were 32 HPV16 positive cases (42%). In comparison with the HPV negative cervical SCC patients, miR-143 was significantly down regulated in the HPV16 positive cervical SCC patients, suggesting that this down regulation might be related with the carcinogenic processes of E6 and E7 genes of HPV16. Researches found that there were 53 miRNAs, including miR-143, which were located at the gene fragile sites and near to the HPV integration sites. Of the HPV integration sites, HPV16 integration site was the most important one . The integration of HPV oncogene to the host cell might influence the formation of miR-143 precursor. In addition, E6 gene of HPV16 could inactivate the tumor suppressor p53, which positively regulated the expression of miR-143 by regulating the synthesis of mature miRNAs . It was also reported that E6 gene of HPV16 could down-regulate the expression of miR-128 .
The traditional treatment for cervical cancer is surgery and radiotherapy. However, the relapse rate is relatively high and there are many complications in these methods. NACT can enhance the efficacy of surgery and radiotherapy, control the lesions of cervical cancer, and reduce the lymph node metastasis rate, parametrial infiltration rate and vascular invasion rate . As previously reported, miRNAs are involved in drug resistance of cancer cells. For example, six miRNAs, including miR-21-5p, miR-20a-5p, miR-103a-3p, miR-106b-5p, miR-143-5p, and miR-215, might be able to predict which patients benefit from adjuvant chemotherapy . The miR-143 increased the sensitivity of human colorectal cancer cells to 5-fluorouracil and the sensitivity of prostate cancer cells to docetaxel [8, 9]. To determine whether miR-143 is sensitive to Taxol treatment in cervical cancer, the changes in the expression of miR-143 and its target protein bcl-2 before and after NACT were detected in 24 patients who were treated effectively. Results showed that there was no significant difference in the expression of miR-143 in cervical cancer tissues after effective chemotherapy, suggesting that miR-143 was not involved in the effective response of cervical cancer tissue to Taxol. In the 24 effective chemotherapy cases, there was no significant decline of the bcl-2 positive expression after chemotherapy, suggesting that bcl-2, was not involved in the response of cervical cancer tissue to Taxol either. Taxol is able to stabilize the tubulin, inhibit the cell division and proliferation, and arrest the cancer cells at G2 and M phases, thus exerting its anticancer effect. The disturbance of the cell apoptosis pathway is beneficial to the tumor growth and invasion. Under the stimulation of cell growth factors, Rb is phosphorylated by the G1 phase protein cyclin D, and releases E2F, which promotes the gene transcription and progression of cell cycle. Studies indicated that miR-143 was one of the regulating genes of cyclin D1 . In cervical cancer, miR-143 may promote apoptosis and inhibit tumor formation by targeting Bcl-2 . Bcl-2 regulates the activation of p53 gene, and prevents the cell from arresting at the G1 phase . Thus miR-143 could regulate cell cycles directly and indirectly to inhibit cancer cell growth, but may not act synergetically with Taxol. The exact relationship between miR-143 expression and cervical cancer sensitivity to Taxol still needs further investigation.
Cervical cancer is widely recognized to be caused primarily by persistent infection with high-risk HPV. However, HPV infection is not sufficient for cervical carcinogenesis and additional genetic events are involved in cervical carcinogenesis. It is reported that the human telomerase gene (hTERC) is involved in the progression of uterine cervical dysplasia to invasive cancer and can be used for the detection of high-grade cervical intraepithelial neoplasia (CIN) [35, 36]. Han et al. reported that immunoreactivities of decreased D2-40 and increased p16INK4A were correlated with higher grade of CIN . Imura et al. found that Laminin-5 was a useful biomarker in the evaluation of invasiveness in cervical adenocarcinoma . In this study, we analyzed the expression of miR-143, the correlation of miR-143 expression with clinical pathological features of cervical cancer, and the sensitivity of miR-143 to Taxol treatment. However, the role of miR-143 expression in evaluating the grade and invasiveness of cervical cancer is not studied and still needs further investigation.
In conclusion, the down regulation of miR-143 was a promoting factor for the occurrence of cervical SCC, and related to the infection of HPV16. The down regulation of miR-143 was also related with tumor size and lymph node metastasis. However, miR-143 was not involved in the effective responses of cervical SCC cells to Taxol.