MicroRNA-218 regulates the epithelial-to-mesenchymal transition and the PI3K/Akt signaling pathway to suppress lung adenocarcinoma progression by directly targeting BMI-1.

OBJECTIVE To investigate the role of miR-218 in the development of lung adenocarcinoma (LA) and its underlying mechanism. PATIENTS AND METHODS Fifty-two pairs of human LA samples and adjacent para-carcinoma tissue samples were collected from our hospital between June 2015 and March 2017. Meanwhile, one normal human pulmonary epithelial cell line BEAS-2B and four human LA cell lines (H1299, PC-9, A549, and SPC-A1) were cultured. The cells' ability of proliferation and migration was detected by MTT assays and Transwell assays, respectively. The target gene was clarified by dual-luciferase reporter assay. The related protein and mRNA expression levels were detected by immunohistochemistry (IHC), Western blot and quantitative real-time polymerase chain reaction (qRT-PCR), respectively. At last, the tumor xenograft model was made for further exploring the mechanism. RESULTS MiR218 expressions were notably reduced in LA tissues in comparison with controls. In addition, the declined miR218 expressions were correlated with the poor OS and worse clinicopathological parameters of LA patients. Furthermore, miR218 overexpression could suppress the proliferation, migration and invasion capacities of LA cells via regulation of PI3K/Akt signaling pathway and epithelial-mesenchymal transition (EMT) respectively. Results in the current study also revealed that miR-218 upregulation could suppress the tumor growth rate and tumor size of LA mice. B-lymphoma Moloney murine leukemia virus insertion region-1 (BMI-1) was confirmed to be a direct target for miR-218 and upregulated in LA tissues, which indicated the poor prognosis of LA patients. CONCLUSIONS MiR-218 exerted anti-tumor functions in LA partially via the regulation of BMI-1, suggesting that BMI-1/miR-218 axis may provide a novel insight into tumorigenesis and the basis for the development of miRNA-targeting therapies against LA.

[1]  M. Alonso-Riaño,et al.  Lung adenocarcinoma during pregnancy: clinical case and literature review , 2019, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[2]  J. Xia,et al.  Oridonin inhibits oral cancer growth and PI3K/Akt signaling pathway. , 2018, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[3]  Qingfeng Ni,et al.  Nectin-4 promotes gastric cancer progression via the PI3K/AKT signaling pathway. , 2018, Human pathology.

[4]  S. Pan,et al.  miR-1290 promotes lung adenocarcinoma cell proliferation and invasion by targeting SOCS4 , 2018, Oncotarget.

[5]  D. Gilot,et al.  miRNA displacement as a promising approach for cancer therapy , 2018, Molecular & cellular oncology.

[6]  X. Liu,et al.  MicroRNA-143 regulates the proliferation and apoptosis of cervical cancer cells by targeting HIF-1α. , 2017, European review for medical and pharmacological sciences.

[7]  N. Kanarek,et al.  Barriers to non-small cell lung cancer trial eligibility , 2017, Contemporary clinical trials communications.

[8]  Kailv Sun,et al.  NCOA5 promotes proliferation, migration and invasion of colorectal cancer cells via activation of PI3K/AKT pathway , 2017, Oncotarget.

[9]  K. Rabe,et al.  Precision Diagnosis and Treatment for Advanced Non-Small-Cell Lung Cancer. , 2017, The New England journal of medicine.

[10]  S. Mowla,et al.  Lower expression of miR-218 in human breast cancer is associated with lymph node metastases, higher grades, and poorer prognosis , 2017, Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine.

[11]  R. Huang,et al.  The EMT spectrum and therapeutic opportunities , 2017, Molecular oncology.

[12]  Zhe Zhang,et al.  miR-218 inhibited tumor angiogenesis by targeting ROBO1 in gastric cancer. , 2017, Gene.

[13]  N. Zhang,et al.  miR-145 inhibits proliferation and migration of breast cancer cells by directly or indirectly regulating TGF-β1 expression. , 2017, International journal of oncology.

[14]  W. Sha,et al.  Bmi-1 promotes the invasion and migration of colon cancer stem cells through the downregulation of E-cadherin , 2016, International journal of molecular medicine.

[15]  Ting Deng,et al.  Onco-miR-130 promotes cell proliferation and migration by targeting TGFβR2 in gastric cancer , 2016, Oncotarget.

[16]  Jiateng Zhong,et al.  miR-96 promotes the growth of prostate carcinoma cells by suppressing MTSS1 , 2016, Tumor Biology.

[17]  A. Hague,et al.  The PI3K/Akt Pathway in Tumors of Endocrine Tissues , 2016, Front. Endocrinol..

[18]  K. Nan,et al.  BMI-1, a promising therapeutic target for human cancer. , 2015, Oncology letters.

[19]  Xiefu Zhang,et al.  MiR-218 regulates cisplatin chemosensitivity in breast cancer by targeting BRCA1 , 2015, Tumor Biology.

[20]  Q. Yao,et al.  miR-15b regulates cisplatin resistance and metastasis by targeting PEBP4 in human lung adenocarcinoma cells , 2015, Cancer Gene Therapy.

[21]  C. M. Eischen,et al.  Differences in miRNA Expression in Early Stage Lung Adenocarcinomas that Did and Did Not Relapse , 2014, PloS one.

[22]  M. Mino‐Kenudson,et al.  High-grade lung adenocarcinomas with micropapillary and/or solid patterns: a review , 2014, Current opinion in pulmonary medicine.

[23]  Fangzhou Song,et al.  Bmi-1 regulates epithelial-to-mesenchymal transition to promote migration and invasion of breast cancer cells. , 2014, International journal of clinical and experimental pathology.

[24]  A. Pandiella,et al.  Activation of the PI3K/mTOR/AKT Pathway and Survival in Solid Tumors: Systematic Review and Meta-Analysis , 2014, PloS one.

[25]  Liang Zhou,et al.  Overexpression of Bmi-1 contributes to the invasion and metastasis of hepatocellular carcinoma by increasing the expression of matrix metalloproteinase (MMP)‑2, MMP-9 and vascular endothelial growth factor via the PTEN/PI3K/Akt pathway. , 2013, International journal of oncology.

[26]  Xinyu Zhao,et al.  shRNA-mediated knockdown of Bmi-1 inhibit lung adenocarcinoma cell migration and metastasis. , 2012, Lung cancer.

[27]  Z. Leng,et al.  Bmi-1 Promotes the Chemoresistance, Invasion and Tumorigenesis of Pancreatic Cancer Cells , 2012, Chemotherapy.

[28]  Libing Song,et al.  Bmi-1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer , 2011, Molecular Cancer.

[29]  R. W. Matheny,et al.  Effects of PI3K catalytic subunit and Akt isoform deficiency on mTOR and p70S6K activation in myoblasts. , 2009, Biochemical and biophysical research communications.

[30]  Libing Song,et al.  Bmi‐1 expression predicts prognosis for patients with gastric carcinoma , 2008, Journal of surgical oncology.

[31]  J. Thiery Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[32]  A. Jemal,et al.  Cancer statistics, 2018 , 2018, CA: a cancer journal for clinicians.

[33]  Hai-tao Xu,et al.  MiR-31 Functions as a Tumor Suppressor in Lung Adenocarcinoma Mainly by Targeting HuR. , 2016, Clinical laboratory.

[34]  P. Savagner Epithelial-mesenchymal transitions: from cell plasticity to concept elasticity. , 2015, Current topics in developmental biology.

[35]  Libing Song,et al.  [Expression and significance of Bmi-1 in breast cancer]. , 2007, Ai zheng = Aizheng = Chinese journal of cancer.