Abstract
MicroRNA-22 (miR-22), a short non-coding RNA that post-transcriptionally regulates mRNA stability and protein synthesis, has been shown to enhance metastatic potential and to suppress HER-3, an important mRNA marker for non-small cell lung cancer (NSCLC). However, the effect of miR-22 has not been investigated in lung adenocarcinoma (LADC), the most common type of NSCLC in the Far East. In this study, we analyzed the role of miR-22 expression in LADC patients. Expression of miR-22 was detected by reverse-transcription polymerase chain reaction (RT-PCR), and confirmed by cDNA sequencing. Signals of miR-22 in LADC sections were identified using in situ hybridization (ISH). The association between miR-22 expression and survival was evaluated by the log-rank test. Induction of miR-22 expression and the effect on HER-3 levels, as well as the subsequent cell behavior were also investigated In vitro. Two types of miR-22: miR-22 and miR-22H, were detected by RT-PCR. The miR-22H had extra 13 bases, 5’-TGTGTTCAGTGGT-3’, at the 3’-end, and this segment was named miR-22E. Using ISH, miR-22E overexpression was detected in 225 (83.0%) of 271 LADC patients. A significant difference was found in cumulative survival between patients with high miR-22E levels and those with low miR-22E levels (p In vitro, epidermal growth factor induced miR-22, but reduced HER-3 expression. Expression of miR-22 increased cell movement ability. In conclusion, expression of miR-22 is closely associated with tumor recurrence, metastasis and overall survival in LADC patients by suppressing HER-3 protein expression to enhance epithelial-mesenchymal transition and metastasis.
Highlights
Recent development of chemotherapy targeting at mutated EGFR has successfully become a major strategic treatment for the lung adenocarcinoma (LADC) [1]
Expression of miR-22 was detected by reverse-transcription polymerase chain reaction (RT-PCR) and in situ hybridization (ISH)
Expression of miR-22 was detected by RT-PCR in all four LADC cell lines (Figure 1(a)), and all five LADC samples examined (Figure 1(b))
Summary
Recent development of chemotherapy targeting at mutated EGFR has successfully become a major strategic treatment for the lung adenocarcinoma (LADC) [1]. Using a data mining to search EGFR-related web documents of LADC, several potential genes have been identified, including DNA repair-, mitochondria transport-, and membrane receptor-associated proteins, such as hepatocyte growth factor (HGF), HGF receptor ( known as c-MET) [3]-[9] and HER-3 ( known as v-ErbB-2 avian erythroblastic leukemia viral oncogene homolog 3, ErbB-3) [10]. HER-2 does not possess ligand-binding site, and HER-3 is lack of cytoplasmic tyrosine kinase activity [12], and the receptor does not transduce signals [11]. Such deficiency suggests that HER-3 may act as a decoy receptor [13] to compete with HER1 and HER-4 [14] [15]. Using statistical software to analyze data from microarray and quantitative reverse-transcription polymerase chain reaction, expression of HER-3 mRNA has been shown to be one of the high risk genes correlated with relapse-free and overall survival of patients with non-small cell lung cancer (NSCLC) [10], though the cell type, which expresses HER-3, has not been identified
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