Expression And Function Of GDF15 And S100A2 In Colorectal Cancer

Colorectal cancer (CRC) is one of common digestive system malignancies. The morbidity and mortality is higher and rising. Although medical technologies have been developed, the effects on prevention and control of malignant tumors are little. There is no significant improvement in 5-year survival rate of advanced colorectal cancer and the mortality rate has not been significantly reduced. Metastasis is a major reason of cancer-related deaths. Therefore, researches on tumor metastasis related genes are critical for predicting early metastasis, reducing metastasis incidence and improving the survival rate of colorectal cancer. Several reports have suggested some diagnostic and prognostic markers in colorectal cancer, whereas the results are inconsistent and the statistical power of individual study is also insufficient. We conducted a meta-analysis study aiming to summarize the diagnostic and prognostic performance of the marker.Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-P (TGF-β) superfamily. The dysregulation of GDF15 expression has been associated with diverse human diseases development and cancer progression. The S100A2 (aliases S100L and CaN19), is a member of the S100 proteins family. S100A2 is frequently dysregulated in neoplastic disorders. The aberrant expression of S100A2 may be important for neoplastic transformation. The expression of S100A2 is related with the tumor size, invasion, migration, differentiation, lymph node metastasis, tumor grade, prognosis and recurrence. The aberrant expression of GDF15 and S100A2 and their involvement in colorectal cancer metastasis are worth studying.1. The role of GDF15 in colorectal cancer metastasisGDF15-Flag vector and GDF15 shRNA were constructed. We transfected GDF15-Flag and found ectopic expression of GDF15 increased migration and invasion of colorectal cancer cells. Ectopic expression of GDF15 increased mesenchymal markers, like Vimentin, MMP9 and Twist, and reduced epithelial markers, like E-cadherin, which was detected by Western Blot and further validated by immunofluorescence assay. GDF15 shRNA rescued the alteration of migration, invasion and EMT markers caused by GDF15 overexpression. GDF15 shRNA inhibited the migration and invasion of colorectal cancer cells. Knockdown of GDF15 increased expression of E-cadherin and reduced the expression of Vimentin in SW620. In addition, rh-GDF15 treatment on GDF15 knockdown cells could recover the migration, invasion and EMT markers in SW620. Thus, GDF15 promoted metastasis through EMT, at least was partly due to EMT pathway. GDF15 overexpression cells and GDF15 knockdown cells were respectively injected into tail vein of NOD/SCE) mice to explore whether GDF15 could affect metastasis of colorectal cancer cell in vivo. In addition, we detected GDF15 level in serum from 353 healthy controls and 287 colorectal cancer patients by ELISA. Serum GDF15 levels in CRC patients were higher than those in healthy subjects. High level of serum GDF15 was correlated with lymph node metastasis, distant metastasis, differentiation and TNM stage. Higher GDF15 expression level was associated with worse overall survival for CRC patients2. GDF15 is a promising diagnostic and prognostic biomarker in colorectal cancer-Meta analysisWe performed the meta-analysis of all relevant available data to explore the diagnostic and prognostic performance of serum GDF15 in CRC. An original study was also conducted to explore the diagnostic and prognostic value of serum GDF15 in CRC patients. We searched PubMed and ISI Web of Knowledge up to November 1st,2014 for eligible studies. In order to explore the diagnostic performance of GDF15, standardized mean difference (SMD) and their 95% confidence intervals (CI) were estimated and receiver-operating characteristic (ROC) curves were constructed. For prognostic meta-analysis, study-specific hazard ratios (HRs) of serum GDF15 for survival were summarized. A total of 8 studies were included in the meta-analyses. Our results revealed that serum GDF15 levels in CRC patients were higher than those in healthy subjects. For discriminating CRC from healthy controls, the AUC of GDF15 was 0.816 (95% CI:0.792-0.838). Besides, higher GDF15 expression level was associated with worse overall survival for CRC patients. In conclusion, the present meta-analysis suggests that serum GDF15 may be a useful diagnostic and prognostic biomarker for CRC.3. The role of S100A2 in colorectal cancerS100A2-pcDNA3.1 vector and S100A2 siRNA were constructed. Ectopic expression of S100A2 increased migration of colorectal cancer cells. Knockdown of S100A2 reduced migration of colorectal cancer cells. Through ELISA, we detected S100A2 level in serum from healthy controls and colorectal cancer patients. Colorectal cancer patients with high serum S100A2 level were related with poor prognosis. Through immunohistochemistry, we detected the expression of S100A2 in colorectal cancer samples. The expression of S100A2 in tumor was related with differentiation. In addition, positive nuclear S100A2 in tumor cells showed a significant relation with differentiation and TNM stage. In addition, we analyzed the relevance between GDF15 and S100A2. There was a positive correlation between GDF15 and S100A2 expression in TNM I/II of CRC. Patients with GDF15-positive/S100A2-positive expression had poorer overall survival than those with GDF15-negative/S100A2-negative expression.According to the study of GDF15 and S100A2 in colorectal cancer, we draw the following conclusions:1. The role of GDF15 in colorectal cancer① Serum GDF 15 levels in CRC patients are higher than those in healthy subjects.② CRC patients with high serum GDF15 level are related with poor prognosis.③ GDF 15 promotes EMT and metastasis in colorectal cancer.2. The role of S100A2 in colorectal cancer① S100A2 could affect migration of colorectal cancer.② The expression of S100A2 in tumor is related with differentiation. In addition, positive nuclear S100A2 in tumor shows a significant relation with differentiation and TNM stage.③ Higher S100A2 expression level is associated with worse overall survival for CRC patients.④ There was a positive correlation between GDF 15 and S100A2 expression in TNM Ⅰ/Ⅱ of CRC. Patients with GDF15-positive/S100A2-positive expression had poorer overall survival than those with GDF 15-negative/S100A2-negative expression.