MicroRNAs 143 and 145 are possible common onco-microRNAs in human cancers

Abstract

Abstract. MicroRNAs (miRNAs) are endogenously expressed RNAs 18-24 nucleotides in length that regulate gene expression through translational repression by binding to a target mRNA. It is thought that the expression level of miRNAs, which act like antioncogenes, is frequently reduced in cancers because of chromosome deletion and epigenetic changes. Since the processing of miRNAs has been characterized to be enzymatic in nature, the expression levels of miRNAs are closely associated with the activity and levels of such enzymes. Here, we found that miRNA 143 and 145 expression levels were extremely reduced in colon cancer cells and commonly in the other kinds of cancer cells tested. The transfection of each precursor miRNA into the cells demonstrated a significant growth inhibition in human colon cancer DLD-1 and SW480 cells, and ERK5 was determined to be the target gene of miRNA 143. Since the presence of genomic loci of the miRNAs was confirmed by PCR in the cell lines and the precursor miRNAs exhibited a growth inhibitory effect in DLD-1 and SW480 cells, the early processes such as transcription and enzymatic modification from primary miRNAs to precursor miRNAs seemed to be commonly disturbed. These findings indicate that the miRNAs 143 and 145 could become good tumor markers and provide an important clue in the study of the mechanism of oncogenesis involving miRNAs.

Role of anti-oncomirs miR-143 and -145 in human colorectal tumors

“…Previously, we reported that miR-143 and -145, which are localized at 5q32 and possibly transcribed as the same primary miRNA, 9 were downregulated in six patients MicroRNA-143 and -145 in human colorectal tumors Y Akao et al with colon cancers; 7 and we found that they function as anti-proliferative miRNAs based on the results of experiments using human colon cancer DLD-1 cells transfected with either miRNA. In this study, the expression levels of miR-143 and -145 in 128 clinical samples of cancers and adenomas were examined by performing TaqMan miRNA assays using real-time PCR.…”

“…We further confirmed that among the various synthetic miR-143BPs the miR-143BP/ 3 0 -2 M was the most potent for the suppression of the protein expression of ERK5, which was previously determined to be one of the major target genes of miR-143 (Figure 2c). [7][8][9][10][11] In contrast, the level of ERK5 mRNA was almost unchanged with all the synthesized miR-143s tested by semi-quantitative reverse transcription PCR (data not shown). Thus, such a modification and change in the duplex structure in miR-143 was closely associated with the potency of its growth-suppressive effect on DLD-1 cells.…”

“…However, the upregulation of miR-7 and -21 and downregulation of miR-34a are significant markers in cancers. ERK5 was already determined to be a target gene of miR-143 by us [7][8][9][10][11] and Esau et al 23 Oncogene K-ras 24 MicroRNA-143 and -145 in human colorectal tumors Y Akao et al checkpoint kinase CHEK2 have also been suggested to be candidate target genes of miR-143. As putative targets of miR-145 with potential oncogenic functions are transcription factors such as MYCN, FOS, YES and FLI, cell-cycle promoters such as cyclin D2 and CDK3 and mitogenactivated protein kinase pathway (MAPK) transduction proteins such as MAP3K3 and MAPK4K4 (http:// microrna.sanger.ac.uk/targets/v5).…”

“…[3][4][5][6] Many miRNAs target mRNAs involved in processes aberrant in tumorigenesis, such as proliferation, survival, cell death and differentiation. In particular, miR-143 and -145 have been shown to function in tumor suppression, because their reduced expression has been observed in most of the human cancer cell lines tested 7 and particularly so in colon cancers 8 and gastric cancers. 9 The enforced expression of both miR-143 and -145 in lowexpression human colon or gastric cancer cells significantly inhibits their cell growth.…”

“…9 The enforced expression of both miR-143 and -145 in lowexpression human colon or gastric cancer cells significantly inhibits their cell growth. 7,9 One of the target genes of miR-143 was determined to be ERK5, which is related to cell growth. [7][8][9][10][11] These findings indicate the antioncogenic role of miR-143 and -145 is commonly in gastrointestinal cancers.…”