Abstract
The actin fiber-associated protein 1-antisense RNA1 (AFAP1-AS1) is upregulated in various cancers and associated with cancer proliferation and metastasis. Several cancer-related pathways have been linked to up-expression of this long non-coding (lnc)RNA, but the underlying mechanisms are yet unknown. In triple negative breast cancer (TNBC), AFAP1-AS1 expression is also significantly overexpressed compared to that in other subtypes of breast cancer from the TCGA dataset. In this study, we performed bioinformatic RNAhybrid analyses and identified that miR-145 is a potential target of AFAP1-AS1 and able to reduce MutT homolog-1 (MTH1) expression. Thus, this study investigated the oncogenic activity of AFAP1-AS1 in TNBC cells and the underlying mechanisms that are yet poorly understood. The results showed that miR-145 expression was low, whereas AFAP1-AS1 and MTH1 expression was high in TNBC cells and that miR-145 mimics reduced TNBC cell proliferation and invasion, whereas miR-145 knockdown exerted the opposite activity in TNBC cells. Moreover, knockdown of AFAP1-AS1 reduced tumor cell proliferation and invasion, but miR-145 co-transfection rescued tumor cell viability and colony formation ability. The dual luciferase reporter assay showed that AFAP1-AS1 could directly target miR-145, while miR-145 could directly target MTH1. After knockdown of ATF6, AFAP1-AS1 was reduced along with AFAP1-AS1 promoter activity. This study revealed that AFAP1-AS1 could promote TNBC cell proliferation and invasion via regulation of MTH1 expression through targeting of miR-145.
Highlights
Long non-coding RNAs are naturally occurring non-coding RNA 200 nucleotides or more in length that play important roles in the regulation of different biological processes of tumors[1,2]
A previous study reported that miR-145 can reduce MutT homolog-1 (MTH1) expression in lung adenocarcinoma and contribute to a significant inhibition of cell proliferation, indicating that miR-145 plays an inhibitory role in lung adenocarcinoma cell through suppression of MTH1 expression
AFAP1-AS1 expression was significantly higher in triple negative breast cancer (TNBC) than in other subtypes of breast cancer using TCGA dataset (Figure S1) We found that expression levels of miR-145 and MTH1 in TNBC were obviously lower and higher than those in luminal breast cancer, respectively (Figures S2 and S3)
Summary
Long non-coding RNAs (lncRNAs) are naturally occurring non-coding RNA 200 nucleotides or more in length that play important roles in the regulation of different biological processes of tumors[1,2]. MiR-145 has been reported to play an important role in the regulation of cancer cell growth, invasion, and metastasis[19,20], and miR145 overexpression was able to inhibit cancer cell growth by downregulating MAP3K1 in lung cancer[21] and the PAK4-dependent pathway in colon cancer[22]. We hypothesized that AFAP1-AS1 overexpression could promote triple negative breast cancer (TNBC) cell proliferation and invasion through competitive binding to miR-145 to, in turn, upregulate MTH1 expression and TNBC cell phenotypes in vitro. First assessed expression of AFAP1-AS1, miR-145, and MTH1 in normal breast cells and different breast cancer cell lines and investigated the differential effects of miR-145 and AFAP1-AS1 on the regulation of breast cancer cell viability and invasion in vitro and in vivo. We explored and confirmed their interactions in breast cancer cells
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