Abstract
BackgroundReduced expression of retinoic acid-induced 2 (RAI2) was found in breast cancer. The regulation and function of RAI2 in human colorectal cancer (CRC) remain unclear.MethodsEight CRC cell lines and 237 cases of primary CRC were analyzed. Methylation-specific PCR (MSP), flow cytometry, xenograft mouse model, and shRNA technique were employed.ResultsRAI2 was completely methylated in RKO, LOVO, and HCT116 cells; partially methylated in HT29 cells; and unmethylated in SW480, SW620, DLD1, and DKO cells. RAI2 was methylated in 53.6% (127/237) of primary colorectal cancer. Methylation of RAI2 was significantly associated with gender (P < 0.001), TNM stage (P < 0.001), and lymph node metastasis (P < 0.001). Analyzing by the Kaplan-Meier method, methylation of RAI2 was significantly associated with poor 5-year overall survival (OS) (P = 0.0035) and 5-year relapse-free survival (RFS) (P = 0.0062). According to Cox proportional hazards model analysis, RAI2 methylation was an independent poor prognostic marker for 5-year OS (P = 0.002) and poor 5-year RFS (P = 0.022). RAI2 suppressed cell proliferation, migration, and invasion and induced cell apoptosis in CRC. In addition, RAI2 inhibited AKT signaling in CRC cells and suppressed human CRC cell xenograft growth in mice.ConclusionRAI2 is frequently methylated in human CRC, and the expression of RAI2 is regulated by promoter region methylation. Methylation of RAI2 is an independent poor prognostic marker of CRC. RAI2 suppresses CRC cell growth both in vitro and in vivo. RAI2 suppresses CRC by inhibiting AKT signaling.
Highlights
Reduced expression of retinoic acid-induced 2 (RAI2) was found in breast cancer
RAI2 is silenced by promoter region hypermethylation in colorectal cancer cells By analyzing The Human Protein Atlas, RAI2 was found to be highly expressed in normal human colonic tissue, and its expression was reduced in colorectal cancer samples
Loss of RAI2 expression was detected in RKO, LOVO, and HCT116 cells, and reduced expression of RAI2 was found in HT29 cells (Fig. 1b)
Summary
Reduced expression of retinoic acid-induced 2 (RAI2) was found in breast cancer. The regulation and function of RAI2 in human colorectal cancer (CRC) remain unclear. The notion that aberrant epigenetic changes are involved in cancer development is widely accepted [3, 4]. Retinoic acid (RA) plays an important role in development, adult hematopoiesis, and cell differentiation [9]. Retinoid-based differentiation therapy of acute promyelocytic leukemia was one of the first successful examples of molecularly targeted treatment strategies [10]. The growth and differentiation of epithelial cells are strongly controlled by retinoid-activated genes.
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