Understanding of the molecular alterations that occur during tumorigenesis, and identification of novel markers for cancer diagnosis and novel targets for treatment, may be important for the improvements in tumor diagnosis, treatment and prevention. This study was focus on human glioma, which is an aggressive tumor with heterogeneous tumor biology, high invasiveness, rapid tumor cell proliferation and poor prognosis. Several genetic and molecular mechanisms of tumorigenesis in gliomas have been explained; however, factors affecting this tumor progression remain unclear. As results of our analysis, there are four points of findings. Firstly, Reg IV was up-regulated in human glioma tissues compared with non-neoplastic brain tissues at both mRNA and protein levels; Secondly, the increased Reg IV expression in glioma tissues was significantly correlated with advanced tumor progression and aggressive clinicopathological features; Thirdly, the results of Kaplan-Meier analyses shown that glioma tissues with high Reg IV expression tend to have poorer overall survival. Finally, the multivariate analysis clearly demonstrated that the high expression of Reg IV was a statistically significant risk factor affecting overall survival in glioma patients, suggesting that Reg IV expression could be a valuable marker of glioma progression and prognosis. To our knowledge, this is the first study to analyze the expression patterns and clinical significance of Reg IV at transcriptional and translational levels in a large number of glioma patients.
Reg genes encode five multifunctional small-secreted proteins, which can act as acute phase reactants, lectins, or antiapoptotic or growth agents [19
]. As a novel member of the Reg family, human Reg IV is mapped to chromosome 1q12-q21, whose cDNA contains an open reading frame of 477
bp encoding a peptide of 158 amino acids with a predicted molecular mass of 18 kD [20
]. Reg IV functions as a potent activator of the EGFR/Akt/AP-1 signaling pathway in several types of cancer cells and increases the expression of Bcl-2, Bcl-xl, and surviving proteins, related to the inhibition of apoptosis, suggesting that it may act as a tissue mitogen or play a role in the cell growth [21
]. Additionally, Reg IV has been found to be colocalized with Ki-67, indicating that it may be involved in the proliferative process of epithelial cells [22
]. Besides this, it also contributes to liver metastasis by inducing the expression of matrix metalloproteinase 7 [23
]. In recent year, accumulating studies on Reg IV had reported its presence and overexpression in numerous cancers. The up-regulation of Reg IV in colorectal adenomas was testified by several different research groups [10
]; Zhang et al.
] also indicated that Reg IV might play an important role in initiating colorectal adenoma, and its detection might be useful in the early diagnosis of colorectal adenoma formation. In gastric carcinogenesis, Zheng et al.
] detected the increased expression of Reg IV from gastric intestinal metaplasia to adenoma, but the decreased expression during the malignant transformation of gastric epithelial cells. These findings revealed that Reg IV expression should be considered as a good biomarker for gastric precancerous lesions. In prostate cancer, Hayashi et al.
found the higher serum Reg IV concentration compared with control individuals, indicating that serum Reg IV represents a novel biomarker for this disease [15
]. In line with these previous studies, our data in the present study demonstrated the up-regulation of Reg IV mRNA and protein in human glioma tissues. Interestingly, we also determined that the Reg IV mRNA expression was closely correlated with its protein expression, suggesting that the up-regulation of Reg IV in gliomas may be primarily caused by transcriptional activation. Additionally, its overexpression was associated with advanced pathological grade and low KPS. These results confirmed the contribution of Reg IV expression to the aggressive progression of human gliomas.
Given above intriguing observation correlating Reg IV up-regulation with advanced tumor progression in human gliomas, we were further interested in studying a potential prognostic value of Reg IV for this malignancy. As the results, overall survival after surgical resection among glioma patients in Reg IV-high group was poorer than those in Reg IV-low group. However, there are some different findings on the relationship between Reg IV expression and survival of patients with cancer. For example, Tamura et al.
] revealed that the positive Reg IV expression might be independently associated with a favorable prognosis in patients with advanced gallbladder carcinoma. In gastric cancer, no statistically significant prognostic effect of Reg IV was found [25
]. These different reports suggest that the contribution of Reg IV expression to the clinical outcome of patients may be different according to the type of malignancy.
In conclusion, our data offer the convince evidence for the first time that Reg IV might accelerate disease progression and act as a candidate prognostic marker for human gliomas. Further elucidation on the roles of Reg IV as tumor promoter in gliomas is worth to be done.