Cervical cancer is the major cause of deaths in women worldwide , and the survival rate is greatly reduced for patients with advanced-stage or metastasis. The diagnosis of cervical cancer is conducted by Papanicolaou test and colposcopy. Systematic screening of high-risk populations will improve poor prognosis of advanced cervical cancer. SCC-Ag is a widely used biomarker for cervical cancer with unsatisfactory diagnosis performance for detection of early-stage (AJCC stages IA, IB, and IIA) cervical cancer [16, 17].
As shown in our study, SCC-Ag showed moderate performances in some analysis groups. If the optimal cut-off was used, as many as 63(57.3%) patients of CESC early stage and 76(40.2%) patients of CESC would be falsely considered as healthy. Additionally, there was no difference of SCC-Ag between healthy control and CIN patients. Therefore, it is necessary to find a new effective biomarker for CESC or to combine with SCC-Ag to improve the diagnostic performance for CESC. In the present study, we found that CXCL10 could play complementary role for SCC-Ag as a potential biomarker in prediction of early CESC.
CXCL10 is a CXC chemokine family protein whose widely known function is participating leukocyte trafficking. Moreover, it also plays important roles in numerous cancers. Studies have shown that CXCL10 has dual effects on tumor progression. It has been reported CXCL10 exert anti-malignancy function by inhibiting angiogenesis and influencing tumor microenvironment [18, 19]. However, emerging reports focused on tumor-promoting ability of CXCL10 by increasing cell proliferation and metastasis [20, 21]. CXCL10 mRNA is highly expressed in various tissues including CESC . However, there was no study have accessed the clinical value of serum CXCL10 in patients with CESC. In this study, we focused on diagnostic value of CXCL10 as a serum biomarker for CESC. Our results showed that serum CXCL10 levels in patients with CESC were significantly upregulated compared with healthy controls, which was consistent with the results from TCGA database that levels of CXCL10 mRNA increased in CESC tissues compared with normal tissues. It has been reported that CXCL10 mRNA was greatly upregulated both in cervical tissues of HPV infected patients with CIN or CESC. Moreover, it has been also demonstrated that CXCL10 and its receptor CXCR3 were expressed by cervical cancer cells . The clinically used cutoff for SCC-Ag is 1.5 ng/ml according to the instruction from the manufacture. The optimal threshold in this study was less than 1.5 ng/ml, which may be due to the different population included in different studies. Elevations are also observed in SCC malignancies, such as the head and neck, esophagus, skin, lung. There was no other study of CXCL10 levels in cervical cancer patients. The ranges of the circulating CXCL10 detected in other study on breast cancer were different from the values in our study. This can be explained by different reagents, expression of CXCL10 in different cancers and the exclusion criteria of the healthy controls in different studies.
These results indicated that CXCL10 was a potential marker of CESC. As an individual biomarker, CXCL10 showed moderate diagnostic performance which was comparable with SCC-Ag, as indicated by the AUC. CXCL10 would not be considered to replace SCC-Ag for diagnose CESC. We investigated the supplemental performance of CXCL10 for SCC-Ag in the early diagnosis of CESC in our study. Obvious improvements were observed in the diagnostic abilities of SCC-Ag for CESC combining with CXCL10, as well as in the diagnosis of CESC early stage, which may be explained by the results that there was no correlation between serum CXCL10 and SCC-Ag. Furthermore, in our study, the serum levels of CXCL10 retained moderate diagnosis capabilities for patients with SCC-Ag-negative CESC. All these results indicated that CXCL10 might provide an essential complement for SCC-Ag. All in all, these data illustrated that the combination of CXCL10 and SCC-Ag was an effective diagnosis biomarker for CESC.
CIN may develop slowly to invasive cervical cancer, so that it is important to detect disease and intervene the progression . As shown in our study, although SCC-Ag had the diagnostic abilities in some analysis groups, it showed no ability in distinguishing CESC SCC-Ag-negative from healthy controls or CIN from healthy controls. However, serum levels of CXCL10 in CIN patients were substantially higher than those in healthy controls, and serum levels of CXCL10 in CESC patients were significantly elevated compared to those in CIN patients. The mechanism for the results has not been completely clear, however it might be explained by the previous report that CXCL10 increased significantly in cervical tissues of HPV infected patients with CIN which might progress into invasive carcinoma and CXCL10 participated in the progression of carcinogenesis . In this study, serum CXCL10 levels after treatment decreased significantly, and serum CXCL10 concentrations at baseline were higher in more advanced tumor stages. One possible explanation for these results might be that the cancer tissues were the major source of serum CXCL10 in patients with CESC. CXCL10 showed moderate diagnostic performance as individual serum CESC marker in distinguishing both CESC patients from control subjects and early-stage CESC patients from control subjects. The results that serum CXCL10 concentrations of the patients with advanced CESC were higher than those with early stages of CESC suggested CXCL10 took apart in the process of CESC progression because tumors with late stages were usually cancers with metastases. Our study concluded serum SCC-Ag and CXCL10 were independent from each other which suggested they might play different roles in CESC progression.
Previous studies have shown that CXCL10 is a potential tumor biomarker of malignant diseases which not only has diagnostic value but also has prognostic value for tumors, such as hepatocellular carcinoma, colorectal cancer, and breast cancer [13, 20, 25]. And no previous studies were related to whether high levels of serum CXCL10 were associated with poor prognosis of patients with CESC. In this study, we mainly focused on discovering and validating biomarker for cervical cancer detection, not refer to prognosis. The result of our study that serum CXCL10 concentrations of patients with late-stage (AJCC stages IIB, III, and IV) CESC were higher than those with early-stage CESC suggested CXCL10 might take part in the progression of CESC and be a prognostic marker of the CESC patients. We need to conduct longitudinal follow-up study of CESC patients to explore the prognostic role of serum CXCL10 levels. There were few previous studies have mentioned the performance of CXCL10 in assessing curative effect. In this study, we tracked the dynamics of serum CXCL10 levels in 10 CESC patients receiving treatment of chemoradiotherapy or chemotherapy. We found that the serum CXCL10 levels in CESC patients with PR response after treatment were significantly different from levels prior to treatment. It is further validation of that CXCL10 is a diagnostic biomarker of cervical cancer. Previous studies reported SCC-Ag was valuable in monitoring of curative efficacy of CESC patients [26, 27]. Moreover, the consistence of changes in CXCL10 levels with PR response was the same as in SCC-Ag levels after treatment, which suggested that CXCL10 might reflect the curative efficacy of CESC patients comparably with SCC-Ag. The samples for accessing treatment response in this study were collected from the patients underwent chemoradiotherapy or chemotherapy. It is necessary to enlarge the sample size and analyze the changes of serum CXCL10 levels before and after surgery to further explore the clinical value of CXCL10 in the curative efficacy of cervical cancer.
In conclusion, our study firstly fully illustrated the potential value of serum CXCL10 as a diagnostic biomarker for CESC. The performance of combination of CXCL10 and SCC-Ag was fully investigated in this study. Serum CXCL10 levels may be a novel and useful predictor for CESC as well as it can improve the diagnostic efficiency of SCC-Ag in prediction of cervical cancer. CXCL10 was still valuable in the diagnosis of SCC-Ag negative CESC. The combination of CXCL10 and SCC-Ag showed significantly improved performance compared with SCC-Ag alone. In conclusion, this study indicated that CXCL10 was a potential serum biomarker as a supplement to SCC-Ag in diagnosing cervical cancer.