CCA refers to those malignancies that originate from the epithelial cells of the bile duct system, and is only inferior to liver cancer. CCA is characterized by jaundice, stomachache, eallbladder enlargement, fever, and ascites. There are no specific clinical manifestations for CCA at early stages, resulting in only a small part of patients could receive the curative resection. The 5-year survival rate of CCA patients is low and the the prognosis is dismal. Thus, new predictor biomarkers are in urgent need to improve the prognosis of CCA patients. So far, some prognostic markers have been identified for CCA patients. For instance, Wu et al. claimed that S100P was a candidate for prognosis, diagnosis and treatment of CCA [22]. In the study of Gu et al., CA9 was identified as a promising prognostic biomarker for CCA [23]. In the present study, we were engaged in finding novel and effective molecule to better improve the prognosis of CCA patients.
RECK gene is discovered by Takahashi et al. in v-ki-ras-transfected NIH3T3 cells in 1998, and locates on human chromosome 9p12-p13 [24]. RECK is about 87 kb in length, including 21 exons and 20 introns. RECK protein consists of 971 amino acids with two hydrophobic regions in the N-terminal and C-terminal, respectively. RECK is a novel metastasis suppressor gene, which plays an important role in maintaining the balance of cell proliferation, differentiation and apoptosis. Moreover, RECK might be implicated in regulating cell growth and tumor invasion, migration and angiogenesis [25]. In addition, the prognostic role of RECK has been identified in several cancers, such as colorectal cancer [26]. So here we attempted to explore the prognostic role of RECK in CCA.
In this retrospective study, the expression levels of RECK mRNA in CCA tissues and adjacent normal controls were measured using qRT-PCR method. The results showed significantly reduced expression of RECK mRNA in CCA samples compared with noncancerous controls, which was consistent with the findings in previous studies. The Chi-square test suggested that RECK down-regulation was affected by invasion depth, lymphatic metastasis, differentiation and TNM stage. With these findings, we hypothesized that RECK might be related with the CCA development and prognosis. Therefore, the Kaplan-Meier and Cox regression analyses were carried out. It could be concluded from the survival curve that patients with low RECK expression were more likely to die than those with high RECK expression. The final Cox regression analysis revealed that RECK was an independent biomarker for the prognosis of CCA patients with both univariate and multivariate analyses.
Though we have identified the predictive role of RECK in CCA, its mechanisms on CCA development and progression have not been well understood. MMPs are composed of over 20 zinc dependent enzymes, which could interact with ECM in tumor cells to destroy connective tissues and induce tumor invasion and migration [27]. Evidence has demonstrated that RECK is an inhibitor of MT1-MMP, MMP-2 and MMP-9 and therefore suppresses the development and progression of tumors [19]. In addition, in the study of Huang et al., RECK was reported to be a binding site of the miR-21, which was associated with cancer cell processes as a tumor suppressor gene [28]. Moreover, there were several investigations indicating that miR-21 was related with CCA occurrence and progression [29, 30]. Therefore, we conjectured that RECK might function on CCA through interacting with miR-21. In a word, the precise mechanism of RECK on CCA development is complex and more further studies are needed in future.