CCA is a fatal disease of bile duct epithelial cells, with dismal prognosis [20]. Due to the delay in early diagnosis, the major of CCA patients are diagnosed with metastatic disease, leading to limited therapeutic effects and poor outcomes [21]. Thus, identification of novel biomarkers for early diagnosis of CCA may be a promising way to improve the prognosis of CCA patients. Like other kinds of tumors, the pathogenesis of CCA is a complex process, with the involvement of various molecules. In the previous studies, number of molecular biomarkers were identified for CCA. In the study of Khoontawad et al., EXT1 was proved to be overexpressed in CCA and showed close correlation with CCA genesis, suggesting its potential as a biomarker for the disease [22]. Tang et al. revealed that up-regulation of EXH2 predicted aggressive clinical characteristics and poor prognosis for patients with CCA, suggesting its prognostic significance for the disease [23]. Boonjaraspinyo et al. reported that the expression of PDGGA was positively correlated with aggressive progression of CCA that might be a candidate biomarker for diagnosis and treatment strategies of the disease [24]. To explore the molecular biomarkers for CCA early detection and prognosis evaluation may be an effective approach to improve the outcomes of the patients. In the current study, we investigated the prognostic significance of serum hTERT for CCA.
The molecular abnormalities in tumorigenesis are mainly involved in independent growth, unlimited replication, aging avoidance, block of growth inhibitory signal and escape of apoptosis. Telomeres play an important role in maintaining chromosome stability and cell activity in different animal cells. In normal cells, telomeres are usually presented with procedural shortening, resulting in the apoptosis and senescence of cells. However, in the immortalized and tumor cells, the telomere lengths are maintained by the activated telomerase, resulting the infinite proliferation and canceration [25]. hTERT, a subunit of telomerase, plays a crucial role in telomerase activity mainly [26, 27]. Overexpression of hTERT has been found in a large number of cancers, as well as cholangiocarcinoma [19, 28]. Furthermore, its expression patterns showed close association with development and progression of cancer. Based on this, we deduced that hTERT might hold the potential to serve as a biomarker for CCA.
In the present study, we investigated the expression of serum hTERT mRNA in CCA patients and healthy controls using qRT-PCR. The results showed that serum hTERT was increased in CCA patients compared with healthy controls. Furthermore, the elevated expression of hTERT was positively associated with poor tumor differentiation, positive distant metastasis and advanced TNM stages. All the data revealed that hTERT played a carcinogenic role in development and progression of CCA. The conclusion was consistent with the previous study [19]. It was reported that hTERT might regulate tumor metastasis via miR-29a-ITGB1 pathway [29]. A related research also reported that hTERT promoted cancer invasion and metastasis through coorperating with c-Myc to upregulate the expression of heparanase [12]. However, the specific oncogenic mechanisms for hTERT in CCA remained unidentified. Further researches were still needed.
In addition, ROC analysis was established to assess the diagnostic performance of serum hTERT in CCA. The result demonstrated that serum hTERT could discriminate between CCA patients and healthy individuals with high diagnostic sensitivity and specificity. Additional to CCA, the predictive function of hTERT was also determined in other malignancies. In gastric cancer, the expression profile of hTERT showed close link with clinical factors and disease-free survival of the patients that might be a potential prognostic biomarker for the cancer [30]. The plasma hTERT mRNA level was significantly different between healthy individuals and prostate cancer cases, and ROC analysis demonstrated that hTERT was an useful non-invasive diagnostic biomarker for the disease [31]. Taken together, hTERT might be a potential molecular biomarker for human cancer that might be widely used for early detection, targeted treatment, and prognosis evaluation in tumor.