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Cited by 40Multiple Myeloma Research and TreatmentsMicroRNA in disease regulationChronic Lymphocytic Leukemia Research

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Downregulation of microRNA‑25‑3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway

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Zi, Youmei, Zhang, Yingzi, Wu, Yanwei, Zhang, Lina, Yang, Ru, Huang, Yan·2020·International Journal of Molecular Medicine
DOI 10.3892/ijmm.2020.4841PMC PMC7834966
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Abstract

Numerous studies have confirmed that microRNAs (miRNAs or miRs) have important roles in cancer biogenesis and development including multiple myeloma (MM). MicroRNA‑25‑3p (miR‑25‑3p) has been proven to promote cancer progression, whereas its functions in MM has not yet been reported, at least to the best of our knowledge. Therefore, the present study aimed to investigate the function of miR‑25‑3p in MM and to identify the potential underlying mechanistic pathway. Herein, it was found that miR‑25‑3p expression was significantly increased in MM tissues and cell lines. The upregulation of miR‑25‑3p was closely associated with anemia, renal function impairment international staging system (ISS) staging and Durie‑Salmon (D‑S) staging. A high level of miR‑25‑3p was predictive of a poor prognosis of patients with MM. In vitro, the knockdown of miR‑25‑3p suppressed the proliferation and promoted the apoptosis of RPMI‑8226 and U266 cells, while the overexpression of miR‑25‑3p exerted opposite effects. In addition, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a well‑known tumor suppressor, was confirmed as a target of miR‑25‑3p in MM cells. Moreover, it was found that the PTEN expression levels were decreased, and inversely correlated with miR‑25‑3p expression levels in MM tissues. Further analyses revealed that the overexpression of PTEN exerted effects similar to those of miR‑25‑3p knockdown, whereas the knockdown of PTEN partially abolished the effects of miR‑25‑3p inhibitor on MM cells. Accompanied by PTEN induction, miR‑25‑3p promoted PI3K/AKT signaling pathway activation in MM cells. Collectively, these findings demonstrate critical roles for miR‑25‑3p in the pathogenesis of MM, and suggest that miR‑25‑3p may serve as a novel prognostic biomarker and therapeutic target of MM.

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Figure 1 miR-25-3p expression is significantly upregulated in MM tissues and MM cell lines. (A) Expression of miR-25-3p was detected in 50 bone marrow tissue samples from MM patients and 10 normal bone marrow tissue samples from healthy donors by RT-qPCR. (B) Expression of miR-25-3p in MM cell lines was determined by RT-qPCR. nPCs cells were used as control cells. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. nPCs. (C) Prognostic value of miR-25-3p for MM patients assessed by Kaplan-Meier analysis. MM, multiple myeloma; nPCs, normal plasma cells.
Figure 1 miR-25-3p expression is significantly upregulated in MM tissues and MM cell lines. (A) Expression of miR-25-3p was detected in 50 bone marrow tissue samples from MM patients and 10 normal bone marrow tissue samples from healthy donors by RT-qPCR. (B) Expression of miR-25-3p in MM cell lines was determined by RT-qPCR. nPCs cells were used as control cells. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. nPCs. (C) Prognostic value of miR-25-3p for MM patients assessed by Kaplan-Meier analysis. MM, multiple myeloma; nPCs, normal plasma cells.CC BY-NC-ND · PubMed Central
Figure 2 Knockdown of miR-25-3p suppresses cell proliferation and induces cell apoptosis. RPMI-8226 and U266 cells were transfected with the miR-25-3p inhibitor or miR-25-3p mimics for 48 h, and the cells were then used for analysis. (A) Transfection efficiency was assessed by RT-qPCR. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. mimics NC group.
Figure 2 Knockdown of miR-25-3p suppresses cell proliferation and induces cell apoptosis. RPMI-8226 and U266 cells were transfected with the miR-25-3p inhibitor or miR-25-3p mimics for 48 h, and the cells were then used for analysis. (A) Transfection efficiency was assessed by RT-qPCR. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. mimics NC group.CC BY-NC-ND · PubMed Central
Figure 3 Overexpression of miR-25-3p promotes cell proliferation and inhibits cell apoptosis. RPMI-8226 and U266 cells were transfected with the miR-25-3p mimics or mimics NC for 48 h, and then cells were used for analysis. (A and B) Cell proliferation was measured by CCK-8 assay at the indicated time points. (C) Expression of PCNA protein was measured by western blot analysis. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group.
Figure 3 Overexpression of miR-25-3p promotes cell proliferation and inhibits cell apoptosis. RPMI-8226 and U266 cells were transfected with the miR-25-3p mimics or mimics NC for 48 h, and then cells were used for analysis. (A and B) Cell proliferation was measured by CCK-8 assay at the indicated time points. (C) Expression of PCNA protein was measured by western blot analysis. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group.CC BY-NC-ND · PubMed Central
Figure 4 PTEN is a direct target of miR-25-3p. (A) Schematic of the PTEN1 3′UTR containing the miR-25-3p binding sites. (B) Luciferase assay of 293T cells co-transfected with Firefly luciferase constructs containing the PTEN wt or mut 3′UTRs and miR-25-3p mimics, mimics NC, miR-25-3p inhibitor or inhibitor NC, as indicated (n=3). Data are presented as the means ± SD of 3 independent experiments. (C and D) RPMI-8226 and U266 cells were transfected with miR-25-3p mimics, mimics NC, miR-25-3p inhibitor or inhibitor NC for 48 h, and the expression levels of PTEN mRNA and protein were determined by RT-qPCR and western blot analysis, respectively. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. mimics NC; ##P<0.01 vs. inhibitor NC. (E) Expression of miR-25-3p in MM cell lines was determined by RT-qPCR. nPCs cells were used as control cells. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. nPCs group. (F) PTEN expression was measured by RT-qPCR in 50 bone marrow tissue samples from MM patients and 10 normal bone marrow tissue samples from healthy donors. P<0.01 vs. healthy donor group. (G) Pearson's correlation analysis was used to analyze the correlation between the expression of PTEN and the expression of miR-25-3p expression in multiple myeloma tissues (r=−0.9118, P<0.01).
Figure 4 PTEN is a direct target of miR-25-3p. (A) Schematic of the PTEN1 3′UTR containing the miR-25-3p binding sites. (B) Luciferase assay of 293T cells co-transfected with Firefly luciferase constructs containing the PTEN wt or mut 3′UTRs and miR-25-3p mimics, mimics NC, miR-25-3p inhibitor or inhibitor NC, as indicated (n=3). Data are presented as the means ± SD of 3 independent experiments. (C and D) RPMI-8226 and U266 cells were transfected with miR-25-3p mimics, mimics NC, miR-25-3p inhibitor or inhibitor NC for 48 h, and the expression levels of PTEN mRNA and protein were determined by RT-qPCR and western blot analysis, respectively. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. mimics NC; ##P<0.01 vs. inhibitor NC. (E) Expression of miR-25-3p in MM cell lines was determined by RT-qPCR. nPCs cells were used as control cells. Data are presented as the means ± SD of 3 independent experiments. **P<0.01 vs. nPCs group. (F) PTEN expression was measured by RT-qPCR in 50 bone marrow tissue samples from MM patients and 10 normal bone marrow tissue samples from healthy donors. P<0.01 vs. healthy donor group. (G) Pearson's correlation analysis was used to analyze the correlation between the expression of PTEN and the expression of miR-25-3p expression in multiple myeloma tissues (r=−0.9118, P<0.01).CC BY-NC-ND · PubMed Central
Figure 5 Overexpression of PTEN inhibits the proliferation and promotes the apoptosis of MM cells. RPMI-8226 and U266 cells were transfected with pcDNA-PTEN or pcDNA-vector for 48 h, and the cells were then used for analysis. (A) Transfection efficiency was assessed by western blot analysis. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. pcDNA-vector group.
Figure 5 Overexpression of PTEN inhibits the proliferation and promotes the apoptosis of MM cells. RPMI-8226 and U266 cells were transfected with pcDNA-PTEN or pcDNA-vector for 48 h, and the cells were then used for analysis. (A) Transfection efficiency was assessed by western blot analysis. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. pcDNA-vector group.CC BY-NC-ND · PubMed Central
Figure 6 Knockdown of PTEN markedly reverses the effects of miR-25-3p inhibition on the proliferation and apoptosis of MM cells. (A) Transfection efficiency was assessed by western blot analysis following si-PTEN transfection in RPMI-8226 and U266 cells. RPMI-8226 and U266 cells were co-transfected with the si-PTEN and miR-25-3p inhibitor for 48 h, and the cells were then used for analysis. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are represented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. miR-25-3p inhibitor.
Figure 6 Knockdown of PTEN markedly reverses the effects of miR-25-3p inhibition on the proliferation and apoptosis of MM cells. (A) Transfection efficiency was assessed by western blot analysis following si-PTEN transfection in RPMI-8226 and U266 cells. RPMI-8226 and U266 cells were co-transfected with the si-PTEN and miR-25-3p inhibitor for 48 h, and the cells were then used for analysis. (B and C) Cell proliferation was measured by CCK-8 assay at the indicated time points. (D) Cell apoptosis was measured by flow cytometry. Data are represented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. miR-25-3p inhibitor.CC BY-NC-ND · PubMed Central
Figure 7 Knockdown of miR-25-3p suppresses the activation of the PTEN/PI3K/AKT pathway. RPMI-8226 and U266 cells were co-transfected with the si-PTEN and miR-25-3p inhibitor for 48 h, and the cells were then used for analysis. (A) The levels of PTEN, p-AKT and p-mTOR were measured by western blot analysis. (B) The bands were semi-quantitatively analyzed using ImageJ software. β-actin protein was used as the inner control of PTEN; the results of phosphorylated proteins were calculated as the ratio of phosphorylated to total protein. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. miR-25-3p inhibitor.
Figure 7 Knockdown of miR-25-3p suppresses the activation of the PTEN/PI3K/AKT pathway. RPMI-8226 and U266 cells were co-transfected with the si-PTEN and miR-25-3p inhibitor for 48 h, and the cells were then used for analysis. (A) The levels of PTEN, p-AKT and p-mTOR were measured by western blot analysis. (B) The bands were semi-quantitatively analyzed using ImageJ software. β-actin protein was used as the inner control of PTEN; the results of phosphorylated proteins were calculated as the ratio of phosphorylated to total protein. Data are presented as the means ± SD of 3 independent experiments. *P<0.05, **P<0.01 vs. inhibitor NC group; ##P<0.01 vs. miR-25-3p inhibitor.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Zi, Y., Zhang, Y., Wu, Y., Zhang, L., Yang, R., & Huang, Y.
Affiliations
  • First Affiliated Hospital of Xinxiang Medical University (CN)
  • Central Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
Corresponding author
Zi, Youmei
ORCID
Venue
International Journal of Molecular Medicine
Publisher
Spandidos Publications
Published
2020-12-31
Volume
47
Issue
3
ISSN
  • 1107-3756 (ISSN-L)
  • 1791-244X
DOI
10.3892/ijmm.2020.4841
PMC
PMC7834966
OpenAlex
W3116250464
Cited by
40
References
0
Citations by year
2025: 10 · 2024: 14 · 2023: 6 · 2022: 8 · 2021: 2
FWCI
2.53
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • International Journal of Molecular Medicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
Keywords
miR-25-3p, multiple myeloma, PTEN, PI3K/Akt signaling, cell proliferation, apoptosis, prognostic factors, therapeutic target, microRNA downregulation, tumor suppressor
MeSH terms
Aged, Female, Humans, Male, Middle Aged, Multiple Myeloma, RNA, Neoplasm, Signal Transduction, Down-Regulation, Gene Expression Regulation, Neoplastic, Apoptosis, Phosphatidylinositol 3-Kinases, MicroRNAs, Cell Line, Tumor, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase

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Zi, Y., Zhang, Y., Wu, Y., Zhang, L., Yang, R., & Huang, Y. (2020). Downregulation of microRNA‑25‑3p inhibits the proliferation and promotes the apoptosis of multiple myeloma cells via targeting the PTEN/PI3K/AKT signaling pathway. International Journal of Molecular Medicine. https://doi.org/10.3892/ijmm.2020.4841