CypA, an 18-kDa cytosolic protein that is ubiquitously expressed in prokaryotes and eukaryotes, is an important component in protein folding. CypA has an activity of peptidylprolyl cis-trans isomerase, which may play important roles in protein folding, trafficking, assembly, immune-modulator and cell signaling. It displays an unusually high expression in several cancer types and correlates with poor outcome of the patients. Overexpression of CypA was first demonstrated in hepatocellular carcinoma in 1998 , then a growing number of reports focus on the role of CypA in cancer. Different types of cancers, including lung cancer, colorectal cancer, pancreatic cancer, breast cancer, squamous cell carcinoma, and melanoma exhibit upregulated CypA [8–13]. Some researchers have investigated the function of CypA during tumor progression, including the stimulation of proliferation, blockade of apoptosis, regulation of metastasis, malignant transformation and drug resistant . In the study of Qi et al. , CypA was differentially expressed between esophageal cancer cell lines and immortal cell line, which suggested that CypA may implicated in the esophageal malignant transformation processes. Even so, the expression and significance of CypA in ESCC remains incompletely understood.
Metastasis is the primary cause of morbidity and mortality in cancer patients. Stable CypA RNA-interfered breast cancer and osteosarcoma cells showed reduced migratory capacity . MMPs were also associated with tumor invasion and migration . MMP9 plays a pivotal role in the degradation of ECM . In a microarray results, MMP9 were found regulated by CypA. RNA interference assay also demonstrates that MMP9 were regulated by CypA in SKHep1 cells . The same result was found by Qian et al. in non-small cell lung cancer . Further more, increased expression of MMP9 was found in ESCC .
In this study, we showed that CypA and MMP9 were highly expressed in ESCC. Both high level of CypA and MMP9 expression significantly correlated with the tumor differentiation and metastasis. So, we may conclude that both CypA and MMP9 have an important role in the progression of ESCC. Next, significant positive correlations (Spearmen rank correlation) were found between the expression status of CypA and that of MMP9. This means MMP9 may be one of CypA related interacting partners, suggesting that CypA may regulate the expression of MMP9 . However, the exact molecular mechanisms remain to be clarified. Overall, the available data so far suggest that CypA pathway may well be related to the genetic changes implicated in ESCC progression.
There are lots of reports about different risk factors in ESCC, including NDRG2, HSPA2, HAX-1, USP9X, and so on [23–27]. The prognostic value of MMP-9 in cancer was also investigated, but there were few reports about that of CypA [28–31]. Although it was found no prognostic significance of CypA in non-small cell lung cancer, but overexpression of CypA was associated with decreased survival in various cancers, including endometrial carcinoma, tongue squamous cell carcinoma, and renal cell carcinoma. However, the prognosis value of CypA in ESCC remains unknown. According to our results, MMP-9 failed to predict patients’ prognosis, whereas CypA was shown to be an independent prognostic indicator in patients with ESCC. Take all these results into consideration, CypA might be available not only as clinical predictors, but also as targets for ESCC treatment. We will focus on both the prognostic and treatment value of CypA in furture.
The current study suggested that the high expression of CypA proteins was associated with important clinicopathological parameters in ESCC. There was a significant positive correlation between the expression status of CypA and that of MMP9. Further, CypA was an important prognostic indicator in cases of ESCC. Therefore, CypA/MMP9 signal pathway may be attributed to the malignant transformation of ESCC, and attention should be paid to a possible target for therapy.