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Cited by 122MicroRNA in disease regulationPI3K/AKT/mTOR signaling in cancerMechanisms of cancer metastasis

PIK3R1 targeting by miR-21 suppresses tumor cell migration and invasion by reducing PI3K/AKT signaling and reversing EMT, and predicts clinical outcome of breast cancer

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YAN, LI-XU, LIU, YAN-HUI, XIANG, JIAN-WEN, WU, QI-NIAN, XU, LEI-BO, LUO, XIN-LAN, ZHU, XIAO-LAN, LIU, CHAO +6 more·2016·International Journal of Oncology
DOI 10.3892/ijo.2015.3287PMC PMC4725461
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Abstract

We have previously shown that dysregulation of miR-21 functioned as an oncomiR in breast cancer. The aim of the present study was to elucidate the mechanisms by which miR-21 regulate breast tumor migration and invasion. We applied pathway analysis on genome microarray data and target-predicting algorithms for miR-21 target screening, and used luciferase reporting assay to confirm the direct target. Thereafter, we investigated the function of the target gene phosphoinositide-3-kinase, regulatory subunit 1 (α) (PIK3R1), and detected PIK3R1 coding protein (p85α) by immunohistochemistry and miR-21 by RT-qPCR on 320 archival paraffin-embedded tissues of breast cancer to evaluate the correlation of their expression with prognosis. First, we found that PIK3R1 suppressed growth, invasiveness, and metastatic properties of breast cancer cells. Next, we identified the PIK3R1 as a direct target of miR-21 and showed that it was negatively regulated by miR-21. Furthermore, we demonstrated that p85α overexpression phenocopied the suppression effects of antimiR-21 on breast cancer cell growth, migration and invasion, indicating its tumor suppressor role in breast cancer. On the contrary, PIK3R1 knockdown abrogated antimiR‑21-induced effect on breast cancer cells. Notably, antimiR-21 induction increased p85α, accompanied by decreased p-AKT level. Besides, antimiR-21/PIK3R1-induced suppression of invasiveness in breast cancer cells was mediated by reversing epithelial-mesenchymal transition (EMT). p85α downregulation was found in 25 (7.8%) of the 320 breast cancer patients, and was associated with inferior 5-year disease-free survival (DFS) and overall survival (OS). Taken together, we provide novel evidence that miR-21 knockdown suppresses cell growth, migration and invasion partly by inhibiting PI3K/AKT activation via direct targeting PIK3R1 and reversing EMT in breast cancer. p85α downregulation defined a specific subgroup of breast cancer with shorter 5-year DFS and OS, which may require more aggressive treatment.

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  • When miR-21 is overexpressed, it leads to downregulation of PIK3R1, resulting in more aggressive tumor behavior.

    “When miR-21 is overexpressed, it leads to the downregulation of PIK3R1, resulting in more aggressive tumor behavior, this relationship is further evidenced by miR-21 knockout models, where the removal of miR-21 restores PIK3R1 activity, leading to reduced PI3K/AKT pathway signaling and, consequently, the inhibition of tumor growth and invasion [39].”

    From miR-21 as a diagnostic and prognostic biomarker in glioma: tissue and serum expression analysis in a Pakistani cohort (2026) · cites this paper as [39]

    The Results section reports that miR-21 overexpression reduced PIK3R1 levels, while inhibiting miR-21 increased PIK3R1 and reduced PI3K/AKT signaling; the paper also links miR-21 targeting of PIK3R1 to breast cancer cell growth and invasion. However, the cited sentence describes miR-21 knockout models, whereas the Methods describe transient knockdown using LNA-antimiR-21, not knockout models. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PIK3R1 is directly targeted and negatively regulated by miR-21.

    “PIK3R1 is directly targeted and negatively regulated by miR-21.”

    From miR-21 as a diagnostic and prognostic biomarker in glioma: tissue and serum expression analysis in a Pakistani cohort (2026) · cites this paper as [39]

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Authors
YAN, L.-X., LIU, Y.-H., XIANG, J.-W., WU, Q.-N., XU, L.-B., LUO, X.-L., ZHU, X.-L., LIU, C., XU, F.-P., LUO, D.-L., MEI, P., XU, J., ZHANG, K.-P., & CHEN, J.
Affiliations
  • Guangdong General Hospital (CN)
  • Guangdong Provincial Hospital of Chinese Medicine (CN)
  • First Affiliated Hospital of Guangzhou Medical University (CN)
  • Sun Yat-sen University (CN)
Corresponding author
  • YAN, LI-XU
  • LIU, YAN-HUI
ORCID
Venue
International Journal of Oncology
Publisher
Spandidos Publications
Published
2015-12-10
Volume
48
Issue
2
Pages
471-484
ISSN
  • 1019-6439 (ISSN-L)
  • 1791-2423
DOI
10.3892/ijo.2015.3287
PMC
PMC4725461
OpenAlex
W2190259787
Cited by
122
References
1
Citations by year
2026: 2 · 2025: 10 · 2024: 11 · 2023: 10 · 2022: 7 · 2021: 9 · 2020: 22 · 2019: 17 · 2018: 12 · 2017: 16 · 2016: 6
FWCI
3.75
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • International Journal of Oncology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81202111)
  • Natural Science Foundation of Guangdong Province
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Keywords
miR-21, PIK3R1, p85α, PI3K/Akt signaling, epithelial-mesenchymal transition, breast cancer, tumor cell migration, tumor invasion, metastasis, microRNA target regulation, disease-free survival, overall survival, prognostic factors
MeSH terms
Breast Neoplasms, Cell Movement, Female, Humans, Neoplasm Invasiveness, Prognosis, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Disease-Free Survival, Phosphatidylinositol 3-Kinases, MicroRNAs, Cell Line, Tumor, Cell Proliferation, Proto-Oncogene Proteins c-akt, Class Ia Phosphatidylinositol 3-Kinase, Epithelial-Mesenchymal Transition, MCF-7 Cells

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