Non-coding microRNA hsa-let-7g as a novel chemoresponse biomarker for S-1 in colon cancer

Abstract

13513 Background: MicroRNAs (miRNAs) are small non-cording RNAs (∼ 22 nucleotide) that regulate gene expression by suppressing their target mRNAs at post-transcriptional level. Previous studies from our group have identified a number of dis-regulated miRNAs due to the loss of p53 tumor suppressor in cancer cell lines. As part of the efforts to further investigate the in vivo biological significance of these miRNAs, the expression of both hsa-let-7g and hsa-miR-200c were investigated using formalin-fixed paraffin embedded (FFPE) colon cancer specimens to evaluate the potential correlation with chemosensitivity and tumorigenesis. Methods: Forty-six patients with recurrent or residual colon cancer lesion assessable were treated with 5-FU based antimetabolite S-1. This includes twenty-one pair of tumor and normal samples. Total RNAs were isolated from these samples FFPE specimens (contains either > 90% normal or > 90% tumor tissue). cDNAs were synthesized using primers specific for hsa-let-7g, hsa-miR-200c and internal control 5S. The expression levels of each particular miRNAs were quantified using real time qRT-PCR analysis. The expression level of each miRNAs was quantified by measuring the difference of threshold cycle (CT) of candidate miRNAs and internal control 5S (Δ-CT). Results: The expression level of hsa-let-7g was significantly higher in tumor tissues compare to normal tissues (p=0.0026; Wilcoxon test). In the forty-six tumor tissues, the expression level of hsa-let-7g in disease response group (patients group of complete response, partial response and no change after chemotherapy) was significantly lower than the disease progression group (p=0.03; Mann-Whitney test). The expression of hsa-miR-200c was significantly over-expressed in tumor tissues compare to normal tissues (p=0.0001; Wilcoxon test). Although hsa-let-7g is strongly associated with patient’s response to S-1 treatment, it is not a prognostic factor for predicting survival. Conclusion: hsa-let-7g and hsa-miR-200c may be associated with tumorigenesis in colon cancer. In addition, hsa-let-7g may be a significant indicator for chemoresponse to S-1 based chemotherapy. No significant financial relationships to disclose.

Relapse-associated microRNA in gastric cancer patients after S-1 adjuvant chemotherapy

“…No study has reported the relationship between gastric cancer, S-1 resistance, and miRNAs. In the study of the relationship between S-1 resistivity and miRNAs in colon cancer, Nakajima et al (14) reported that let-7g and miR-181b are strongly associated with the response to S-1 chemotherapy. In their report, 69.6% (32/46) patients underwent S-1 chemotherapy and 30.4% (14/46) patients underwent S-1 plus cisplatin chemotherapy.…”

Down‐regulation of the microRNA processing enzyme Dicer is a prognostic factor in human colorectal cancer

“…22,23,[27][28][29][30] Regarding colorectal cancer, recent studies have demonstrated differential expression of miRNAs in colorectal cancer compared to normal tissue, and showed miRNA diagnostic and prognostic potential as well as association with chemoresponse. [31][32][33][34][35] Reduced levels of mature ⁄ fully processed miR-143 and miR-145 have been reported in colorectal neoplasia compared to normal tissues, whereas equal abundance of their precursors was observed in both tissues, 36 a finding that might suggest involvement of miRNA processing machinery as a post-transcription event contributing to this reduction. A comparison of Dicer mutant human colorectal cancer cell lines to their corresponding parental cell lines has revealed reduced levels of mature miRNAs with accumulation of their precursors; 55 of 97 known miRNAs were Expression of Dicer in colorectal cancer 557 expressed differentially between Dicer mutant cells and wild-type cells, suggesting that Dicer is required for the biogenesis of a subset of miRNAs.…”

MicroRNA‐143 reduces viability and increases sensitivity to 5‐fluorouracil in HCT116 human colorectal cancer cells

“…Nevertheless, 5-FU alters the expression of a set of 22 miRNAs in colon cancer cell lines [22]. Furthermore, S-1, a fourth-generation 5-FU-based oral drug developed to improve efficacy, also alters the expression levels of certain miRNAs, as demonstrated in tumour tissue from patients undergoing S-1 therapy [24].…”