| Colorectal cancer is the third most frequently diagnosed carcinoma and the fourth as a cause of cancer-related death worldwide. Despite the progress in the diagnosis and treatment of CRC have been substantial, patients often suffer from local recurrence and metastasis. The inhibitors of apoptosis protein (IAP) family has been demonstrated to be crucial in apoptosis resistence in a wide range of malignancy. These proteins are distinguished by the presence of up to three copies of Baculo viral IAP Repeat (BIR) domain. The IAPs have been proved to bind to and suppress a variety of pro-apoptotic factors, thereby effectively inhibit apoptosis in cancer cells. Baculo viral inhibition of apoptosis protein repeat containing 6 (BIRC6) is the largest member of the IAP family. In addition to its IAP activity, BIRC6 has the distinctive property of acting as a chimeric E2/E3 ubiquitin ligase in mammals. Large amount of evidence showed that BIRC6 was highly expressed in several types of cancer and related to the carcinogenesis and prognosis of brain cancer, childhood de novo acute myeloid leukemia, breast cancer and prostate cancer. Preliminary investigations demonstrated that the expression of BIRC6 were more abundant in CRC tissues than in non-neoplastic tissues using cDNA microarrays. Similar results were found by comparing the proteomes of colon cancer stem cells and their differentiated cells. However, there have been no reports of its prognostic relevance based on clinical data and biological function of BIRC6 in CRC cell lines.Part 1:The relation of BIRC6 expression with clinicopathologic characteristics and prognosis of CRCWe examined the expression of BIRC6 in 20 paired CRC and adjacent non-tumorous tissues by Western blot. The expression of BIRC6 in the tumor tissues was significantly higher than that in the adjacent non-tumorous tissues, which was testified meaningful by paired t test. Meanwhile, immunohistochemistry for BIRC6 in 126 paired CRC and adjacent non-tumorous tissues also indicated the similar results, which was statistically meaningful. Cox proportional hazards regression analysis showed that BIRC6 expression in the tumor tissues was an independent prognostic factor for both OS and DFS. Kaplan-Meier method (log-rank test) utilized for survival analysis indicated that the patients with high expression of BIRC6 had a significantly decreased overall survival rate and disease-free survival rate than those with low BIRC6 expression. Subsequently,χ2 test showed that the expression of BIRC6 in the tumor tissues correlated with tumor size and invasion depth. These data indicated that BIRC6 could be a predictive marker of CRC.Part 2:The biological roles of BIRC6 in carcinogenesis and progress of CRCStable BIRC6-knockdown cell lines were established to explore the biological roles of BIRC6 in CRC. Compared with the control cells, BIRC6 down-regulation inhibited cell proliferation and affected cell cycle distribution. Moreover, down-regulation of BIRC6 could promote apoptosis when cooperated with CDDP or 5-FU. These data proved that BIRC6 contributed to proliferation of CRC, which could explained the poor prognosis in CRC patients with up-regulated BIRC6 level according to the result of the first part.In conclusion, this study provided evidence for the first time that BIRC6 could promote cell proliferation in CRC cell lines, and this is the first study showing BIRC6 as an independent predictive marker of survival and recurrence in CRC patients after tumor resection. We believe that BIRC6 could be a novel diagnostic marker and therapeutic target for CRC, and further investigations in this field are needed. |
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