Non-small cell lung cancer (NSCLC) is a malignant tumor with a high fatality, low overall cure, and survival rates worldwide. When only palliative therapy is available, the disease leads to malignant proliferation. Previous studies showed miR-29b serves as an NSCLC suppressor by inhibiting cells proliferation, migration, and invasion. However, the mechanism underlying NSCLC progression remains elusive. In this study, we identified Striatin 4 (STRN4), a target of miR-29b, which serves as a pro-oncogenic protein by promoting cells proliferation, migration, and invasion in NSCLC. Besides, the STRN4 was highly expressed in NSCLC and negatively regulated by miR-29b. Down-regulation of STRN4 inhibits NSCLC cells proliferation, migration, invasion, and promotes apoptosis in vitro, whereas overexpression-induced enhanced cell migration and invasion could be reverved by miR-29b. Notably, overexpression of miR-29b and down-regulation of STRN4 by shRNA suppressed cellular proliferation and delayed tumor progression in vivo. Together, these findings identify a miR-29b/STRN4 regulatory pathway in NSCLC progression, which may provide a new sight for the treatment of NSCLC.
This is a preview of subscription content, log in to check access.
Buy single article
Instant unlimited access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
All data necessary to understand and assess the conclusions of this study are available in the main text. There are no restrictions on data availability in the manuscript.
Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.
Herbst RS, et al. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446–54.
Ambros V. MicroRNA pathways in flies and worms: growth, death, fat, stress, and timing. Cell. 2003;113(6):673–6.
Volinia S, et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci. 2006;103(7):2257–61.
Jiang H, et al. Diverse roles of miR-29 in cancer. Oncol Rep. 2014;31(4):1509–16.
Wang Y, et al. The role of miRNA-29 family in cancer. Eur J Cell Biol. 2013;92(3):123–8.
Suda K, et al. Biological and clinical significance of KRAS mutations in lung cancer: an oncogenic driver that contrasts with EGFR mutation. Cancer Metastasis Rev. 2010;29(1):49–60.
Thakur S, Brenner C. KRAS-driven miR-29b expression is required for tumor suppressor gene silencing. Oncotarget. 2017;8(43):74755–66.
Ling Q, et al. Special suppressive role of miR-29b in HER2-positive breast cancer cells by targeting Stat3. Am J Transl Res. 2015;7(5):878–90.
Zhang L, et al. The relationship between microRNAs and the STAT3-related signaling pathway in cancer. Tumor Biol. 2017;39(7):1–11.
Li Y, et al. Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer. Oncotarget. 2017;8(9):14655–65.
Wang H, et al. MicroRNA-29b attenuates non-small cell lung cancer metastasis by targeting matrix metalloproteinase 2 and PTEN. J Exp Clin cancer Res. 2015;34(59):1–12.
Chen B, et al. A regulatory circuitry comprising TP53, miR-29 family, and SETDB1 in non-small cell lung cancer. Biosci Rep. 2018;38(5):1–10.
Tang Y, et al. Radiation-induced miR-208a increases the proliferation and radioresistance by targeting p21 in human lung cancer cells. J Exp Clin cancer Res. 2016;35(7):1–14.
Mizuno K, et al. Tumor-suppressive microRNA-29 family inhibits cancer cell migration and invasion directly targeting LOXL2 in lung squamous cell carcinoma. Int J Oncol. 2016;48(2):450–60.
Bartoli M, et al. Interaction of calmodulin with striatin, a WD-repeat protein present in neuronal dendritic spines. J Biol Chem. 1998;273(35):22248–53.
Gaillard S, et al. Targeting of proteins of the striatin family to dendritic spines: role of the coiled-coil domain. Traffic. 2006;7(1):74–84.
Gaillard S, et al. Striatin, a calmodulin-dependent scaffolding protein, directly binds caveolin-1. FEBS Lett. 2001;508(1):49–52.
Castets F, et al. Zinedin, SG2NA, and striatin are calmodulin-binding, WD repeat proteins principally expressed in the brain. J Biol Chem. 2000;275(26):19970–7.
Bartoli M, et al. Down-regulation of striatin, a neuronal calmodulin-binding protein, impairs rat locomotor activity. J Neurobiol. 1999;40(2):234–43.
Kachidian P, et al. Relationships between striatin-containing neurons and cortical or thalamic afferent fibres in the rat striatum. An ultrastructural study by dual labelling. Neuroscience. 1998;85(1):111–22.
Salin P, et al. Distribution of Striatin, a newly identified calmodulin-binding protein in the rat brain: an in situ hybridization and immunocytochemical study. J Comp Neurol. 1998;397(1):41–59.
Wong M, et al. Silencing of STRN 4 suppresses the malignant characteristics of cancer cells. Cancer Sci. 2014;105(12):1526–32.
Collins CS, et al. A small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase. Proc Natl Acad Sci. 2006;103(10):3775–80.
Hyodo T, et al. Misshapen-like kinase 1 (MINK1) is a novel component of striatin-interacting phosphatase and kinase (STRIPAK) and is required for the completion of cytokinesis. J Biol Chem. 2012;287(30):25019–29.
Shitashige M, et al. Traf2-and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70(12):5024–33.
Fan C, et al. MicroRNA-873 inhibits colorectal cancer metastasis by targeting ELK1 and STRN4. Oncotarget. 2019;10(41):4192–204.
Sartini D, et al. Pokemon proto-oncogene in oral cancer: potential role in the early phase of tumorigenesis. Oral Dis. 2015;21(4):462–9.
Rheinbay E, et al. Recurrent and functional regulatory mutations in breast cancer. Nature. 2017;547(7661):55–60.
Molina JR et al., Non-small cell lung cancer epidemiology, risk factors, treatment, and survivorship, Mayo Clinic Proceedings. Amsterdam: Elsevier; 2008, pp. 584–594.
Fabbri M, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci. 2007;104(40):15805–10.
Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33.
Fabian MR, et al. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–79.
Jiang F, et al. Pro-oncogene pokemon promotes prostate cancer progression by inducing STRN4 expression. J Cancer. 2019;10(8):1833–45.
Madsen CD, et al. STRIPAK components determine mode of cancer cell migration and metastasis. Nat Cell Biol. 2015;17(1):68–80.
Gautschi O, et al. Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer. 2007;55(1):1–14.
Li Y, et al. Curcumin inhibits human non-small cell lung cancer A549 cell proliferation through regulation of Bcl-2/Bax and cytochrome C. Asian Pac J Cancer Prev. 2013;14(8):4599–602.
Jiang H, et al. Paris saponin I induces apoptosis via increasing the Bax/Bcl-2 ratio and caspase-3 expression in gefitinib-resistant non-small cell lung cancer in vitro and in vivo. Mol Med Rep. 2014;9(6):2265–72.
Chakraborty S, et al. Restoration of p53/miR-34a regulatory axis decreases survival advantage and ensures Bax-dependent apoptosis of non-small cell lung carcinoma cells. FEBS Lett. 2014;588(4):549–59.
Jung O, et al. Timosaponin AIII inhibits migration and invasion of A549 human non-small-cell lung cancer cells via attenuations of MMP-2 and MMP-9 by inhibitions of ERK1/2, Src/FAK and β-catenin signaling pathways. Bioorg Med Chem Lett. 2016;26(16):3963–7.
Bae G-Y, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4(12):2512–22.
We are grateful to the supporting from the Science and Technology Program for Public Wellbeing of Chengdu (2015-HM01-00224-SF). We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
Conflict of interest
The authors declare no potential conflicts of interest.
Written informed consent was obtained from all the participants. The protocols for human specimen studies were approved by the Ethics Committee of the West China Second University Hospital of Sichuan University, and were conducted in agreement with the principles set forth in the Declaration of Helsinki. All animal protocols were approved by the Animal Care and Use Committee of the West China Second University Hospital of Sichuan University.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Xie, Y., Zhao, F., Zhang, P. et al. miR-29b inhibits non-small cell lung cancer progression by targeting STRN4. Human Cell 33, 220–231 (2020). https://doi.org/10.1007/s13577-019-00305-w
- Non-small cell lung cancer