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Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer.

ABSTRACT: Genetic mutation, chromosomal rearrangement and copy number amplification are common mechanisms responsible for generating gain-of-function, cancer-causing alterations. Here we report a new mechanism by which premature cleavage and polyadenylation (pPA) of RNA can produce an oncogenic protein. We identify a pPA event at a cryptic intronic poly(A) signal in MAGI3, occurring in the absence of local exonic and intronic mutations. The altered mRNA isoform, called MAGI3(pPA), produces a truncated protein that acts in a dominant-negative manner to prevent full-length MAGI3 from interacting with the YAP oncoprotein, thereby relieving YAP inhibition and promoting malignant transformation of human mammary epithelial cells. We additionally find evidence for recurrent expression of MAGI3(pPA) in primary human breast tumors but not in tumor-adjacent normal tissues. Our results provide an example of how pPA contributes to cancer by generating a truncated mRNA isoform that encodes an oncogenic, gain-of-function protein.

SUBMITTER: Ni TK

PROVIDER: S-EPMC4905742 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer.

Ni Thomas K TK Kuperwasser Charlotte C

eLife 20160520

Genetic mutation, chromosomal rearrangement and copy number amplification are common mechanisms responsible for generating gain-of-function, cancer-causing alterations. Here we report a new mechanism by which premature cleavage and polyadenylation (pPA) of RNA can produce an oncogenic protein. We identify a pPA event at a cryptic intronic poly(A) signal in MAGI3, occurring in the absence of local exonic and intronic mutations. The altered mRNA isoform, called MAGI3(pPA), produces a truncated pro ...[more]

PMID: 27205883

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Project description:Prenylated rab acceptor 1 domain family member 2 (PRAF2) acts as an oncogene and is closely related to the occurrence and development of various tumors. The present study aimed to clarify the functional relevance of PRAF2 in the biological behaviors of breast cancer by determining the expression of PRAF2 in breast cancer tissues and the corresponding adjacent tissues. The gene phenotypes of PRAF2 in patients with breast cancer in The Cancer Genome Atlas database were predicted using a cancer data online analysis website: The University of Alabama at Birmingham Cancer Data Analaysis Portal (UALCAN). The mRNA and protein expression of PRAF2 was further examined in 37 pairs of fresh frozen breast cancer tissues and adjacent non-tumor tissues by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. High expression of PRAF2 was verified by RT-qPCR in the breast cancer cell line, MCF-7, and small interfering RNA (siRNA) technology was used to silence PRAF2. In the in vitro cell functional experiment, three groups were used: Negative control (NC) group, siRNA-NC group and siRNA-PRAF2 group. Cell Counting Kit-8 (CCK-8) and colony formation assays were conducted to analyze the effect of downregulation of PRAF2 on the proliferation of breast cancer cells. Transwell invasion and cell scratch assays were performed to examine the effect of downregulation of PRAF2 on the invasion and migration of breast cancer cells. UALCAN analysis results indicated that PRAF2 expression was upregulated in breast cancer compared with normal tissue samples (P<0.001). High expression of PRAF2 in breast cancer was associated with TNM stage and regional lymph node metastasis. RT-qPCR results showed increased mRNA expression of PRAF2 in clinical tissue samples from 37 patients with breast cancer, compared with normal adjacent tissues (P<0.001). Protein expression of PRAF2 was also shown to be higher in the breast cancer MCF-7 cells than in the MDA-MB-231 cells. Western blotting analysis combined with ImageJ software quantification showed that the relative expression of PRAF2 protein was significantly higher in clinical tissue samples from 37 patients with breast cancer (1.9750±0.0103) than that in normal adjacent tissues (0.9818±0.0140) (P<0.001). Western blotting analysis results indicated that transfection with siRNA PRAF2 in MCF-7 cells decreased PRAF2 expression (P<0.001). The results of CCK-8 and colony formation assays revealed that downregulation of PRAF2 expression suppressed the proliferation of MCF-7 cells (P<0.05 and P<0.001, respectively). In addition, Transwell invasion and cell scratch assay results showed that downregulation of PRAF2 expression in MCF-7 cells repressed invasion and migration of cancer cells (P<0.001). Overall, PRAF2 expression was significantly higher in breast cancer tissues than normal adjacent tissues, and was closely related to TNM stage and regional lymph node metastasis in breast cancer. PRAF2 was found to act as an oncogene that is able to promote breast cancer cell proliferation and invasion. Thus, PRAF2 may be a potential prognostic factor in patients with breast cancer and a potential target for the treatment of breast cancer metastasis.

Dataset Information

Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer.

Publications

Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer.

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