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Purpose: Secreted protein acidic and rich in cysteines-like 1 (SPARCL1) is an extracellular matrix glycoprotein with malignancy-suppressing potential. The hypothesis that SPARCL1 reduces cancer invasiveness and predicts better survival in colorectal cancers (CRC) was investigated. Experimental Design: Stable SPARCL1 transfectants, RKO-SPARCL1, and corresponding vector control were constructed and implanted into nude mice to generate a mouse xenograft model of liver metastasis. Also, a retrospective outcome study was conducted on the COH set (222 CRCs) and ZJU set (412 CRCs). The protein expression level of SPARCL1 was determined by immunohistochemistry. The Kaplan–Meier and Cox analyses were used for survival analysis. The association of SPARCL1 with mesenchymal–epithelial transition (MET) was examined by reverse transcription PCR (RT-PCR) and Western blot analysis. Results: The ectopic expression of SPARCL1 significantly reduced the potential for anchorage-independent growth, migration, invasion and induced cell differentiation in RKO and SW620 cells. In mouse xenograft model, the expression of SPARCL1 significantly reduced the liver metastasis (P < 0.01). The patient-based studies revealed that the expression of SPARCL1 was related to better differentiation (P < 0.01), less lymph node involvement [OR, 0.67; 95% confidence interval (CI), 0.45–1.00], and less distant metastasis (OR, 0.38; 95% CI, 0.18–0.79). The Kaplan–Meier and Cox analysis showed that the expression of SPARCL1 was associated with better overall survival (log-rank: P < 0.01; HR, 0.57; 95% CI, 0.39–0.84). Transfection of SPARCL1 induced MET of colon cancer cells. Conclusion: SPARCL1 functions as a tumor suppressor promoting differentiation possibly via MET, which inhibits the aggressiveness of CRCs. Clin Cancer Res; 18(19); 5438–48. ©2012 AACR.

Purpose: This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC). Experimental Design: This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan–Meier analysis and COX proportional hazard model were employed to analyze the survivability. Results: Multivariate logistic analysis indicated that the expression of HMGA2 significantly correlates with distant metastasis in training set (odds ratio, OR = 3.53, 95% CI: 1.37–9.70) and validation set (OR = 6.38, 95% CI: 1.47–43.95). Survival analysis revealed that the overexpression of HMGA2 is significantly associated with poor survival of CRC patients (P < 0.05). The adjusted HRs for overall survival were 2.38 (95% CI: 1.30–4.34) and 2.14 (95% CI: 1.21–3.79) in training and validation sets, respectively. Further investigation revealed that HMGA2 delays the clearance of γ-H2AX in HCT-116 and SW480 cells post γ-irradiation, which supports our finding that CRC patients with HMAG2-positive staining in primary tumors had augmented the efficacy of adjuvant radiotherapy (HR = 0.18, 95% CI: 0.04–0.63). Conclusion: Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy. Clin Cancer Res; 17(8); 2570–80. ©2011 AACR.