HAI-BING SUN

Accumulating evidence has shown that micro-RNAs (miRNAs) are involved in multiple processes in cancer development and progression. Upregulation of miRNA-494 (miR-494) has been identified as an oncogenic miRNA and is associated with poor prognosis in several types of human cancer. However, the specific function of miR-494 in colorectal cancer remains unclear. In this study we found that the expression of miR-494 in colorectal cancer tissues and cell lines was much higher than in normal control tissues and cells, respectively. In addition, upregulation of miR-494 more frequently occurred in tissue specimens with adverse clinical stage and the presence of distant metastasis. Moreover, multivariate survival analyses demonstrated that overexpression of miR-494 is an independent prognostic factor for both progression-free and overall survival. In addition miR-494 promoted invasion and migration in colorectal cancer cells, and miR-494 directly inhibited the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression by targeting its 3'-untranslated region (3'-UTR). Moreover, PTEN is down regulated and inversely correlated with miR-494 expression in tissues. Thus, for the first time, we provided convincing evidence that upregulation of miR-494 was associated with tumor aggressiveness and tumor metastasis and promoted cell migration and invasion by targeting PTEN gene in colorectal cancer, and miR-494 is an independent prognostic marker for colorectal cancer patients.

A drug-induced resistant cancer cell is different from its parent cell in transcriptional response to drug treatment. The distinct transcriptional response pattern of a drug-induced resistant cancer cell to drug treatment might be introduced by acquired DNA methylation aberration in the cell exposing to sustained drug stimulation. In this study, we performed both transcriptional and DNA methylation profiles of the HCT-8 wild-type cells (HCT-8/WT) for human colorectal cancer (CRC) and the 5-fluorouracil (5-FU)-induced resistant cells (HCT-8/5-FU) after treatment with 5-FU for 0, 24 and 48 h. Integrated analysis of transcriptional and DNA methylation profiles showed that genes with promoter hypermethylation and concordant expression silencing in the HCT-8/5-FU cells are mainly involved in pathways of pyrimidine metabolism and drug metabolism-cytochrome P450. Transcriptional analysis confirmed that genes with transcriptional differences between a drug-induced resistant cell and its parent cell after drug treatment for a certain time, rather than their primary transcriptional differences, are more likely to be involved in drug resistance. Specifically, transcriptional differences between the drug-induced resistant cells and parental cells after drug treatment for 24 h were significantly consistent with the differentially expressed genes (termed as CRG5-FU) between the tissues of nonresponders and responders of CRCs to 5-FU-based therapy and the consistence increased after drug treatment for 48 h (binomial test, P-value=1.88E−06). This study reveals a major epigenetic mechanism inducing the HCT-8/WT cells to acquire resistance to 5-FU and suggests an appropriate time interval (24–48 h) of 5-FU exposure for identifying clinically relevant drug resistance signatures from drug-induced resistant cell models.