Differential expression ofmiR-1, a putative tumor suppressing microRNA, in cancer resistant and cancer susceptible mice

Abstract

Mus spretus mice are highly resistant to several types of cancer compared to Mus musculus mice. To determine whether differences in microRNA (miRNA) expression account for some of the differences in observed skin cancer susceptibility between the strains, we performed miRNA expression profiling of skin RNA for over 300 miRNAs. Five miRNAs, miR-1, miR-124a-3, miR-133a, miR-134, miR-206, were differentially expressed by array and/or qPCR. miR-1 was previously shown to have tumor suppressing abilities in multiple tumor types. We found miR-1 expression to be lower in mouse cutaneous squamous cell carcinomas (cSCCs) compared to normal skin. Based on the literature and our expression data, we performed detailed studies on predicted miR-1 targets and evaluated the effect of miR-1 expression on two murine cSCC cell lines, A5 and B9. Following transfection of miR-1, we found decreased mRNA expression of three validated miR-1 targets, Met, Twf1 and Ets1 and one novel target Bag4. Decreased expression of Ets1 was confirmed by Western analysis and by 3’ reporter luciferase assays containing wildtype and mutated Ets1 3’UTR. We evaluated the effect of miR-1 on multiple tumor phenotypes including apoptosis, proliferation, cell cycle and migration. In A5 cells, expression of miR-1 led to decreased proliferation compared to a control miR. miR-1 expression also led to increased apoptosis at later time points (72 and 96 h) and to a decrease in cells in S-phase. In summary, we identified five miRNAs with differential expression between cancer resistant and cancer susceptible mice and found that miR-1, a candidate tumor suppressor, has targets with defined roles in tumorigenesis.

Prognostic significance of miRNA‐1 (miR‐1) expression in patients with chordoma

“…More recently studies have found several other deregulated miRs in chordoma, including miR‐31, miR‐222, miR‐140‐3p, miR‐148a, and miR‐149‐3p . Among these miRs with deregulated expression in chordoma, miR‐1 is a validated and frequently downregulated in various types of cancer . In the present study, we characterized 35 chordoma specimens and extracted RNAs to quantify the relative expression level of miR‐1.…”

“…The results showed miR‐1 expression was inversely correlated with Met expression; expression of miR‐1 was lower in chordoma tissues and was coupled with high expression of Met. These results are consistent with studies in other types of human cancers such as colorectal tumors which also show that miR‐1 and Met are often concomitantly deregulated …”

“…Previous studies have shown that miR‐1 is involved in the control of Met expression in several tumor cells including osteosarcoma and chordoma . Because Met overexpression is not due to gene amplification in the examined chordoma samples, and it is known that miR‐1 negatively regulates Met, we evaluated if downregulation of miR‐1 in chordoma samples was correlated to Met up‐regulation.…”

“…miR‐1‐1 and miR‐1‐2 are located in two distinct chromosomal regions in human genome, 20q13.33 and 18q11.2, respectively, but both are processed into an identical mature form of miR‐1. The decrease or loss of miR‐1 expression and the overexpression of Met have been related to invasive growth or increased tumor stages in several human cancers . However, whether the expression of miR‐1 can be a prognostic biomarker in chordoma has not been investigated.…”

Extracellular Vesicles Modulate the Glioblastoma Microenvironment via a Tumor Suppression Signaling Network Directed by miR-1

“…Tumor suppressive functions of miR-1 have been demonstrated in numerous human malignancies (17, 39-41). Its action was associated with direct targeting of several oncogenes, including MET (30) – one of the crucial oncogenic drivers in GBM.…”