The role of Nuclear Enriched Abundant Transcript 1 (NEAT1) in non-small cell lung cancer’s drug resistance
Introduction. Lung cancer is the leading cause of cancer related mortality worldwide.3 Non-small cell lung cancer (NSCLC) makes up 70-80% of all lung cancer cases.7 Unfortunately, nearly 50% of individuals who are diagnosed with stage I NSCLC die within 10 years of the diagnosis.7 A long non-coding RNA called, Nuclear enriched abundant transcript 1 (NEAT1), is associated with poor differentiation, lymph node metastasis and advance TMN stage in NSCLC.7 In addition, NEAT1 is thought to be involved in development of resistance to drugs such as Paclitaxel in NSCLC.4 NEAT1 is the target of a tumor-suppressor microRNA called miR-449a, which is downregulated in lung cancer.5 Unfortunately, the exact mechanism by which NEAT1 confers drug resistance in NSCLC is fairly unknown. However, recent studies have shown that NEAT1 could contribute to progression and drug resistance of NSCLC through upregulation of Wnt/b-Catenin and akt/mTOR pathway.2,3,7 Methods. In one experiment, the level of expression of miR-101-3p was compared between NSCLC cells with wild-type NEAT1 and NSCLC cells with NEAT1 knockdown.3 In addition, SOX9 protein expression was analyzed in NSCLC cells with and without NEAT1 knockdown by western blot.3 In the second experiment, the level of expression of NEAT1 in renal mesangial cells of both normal and diabetic rats were compared.2 Moreover, the level of expression of akt and mTOR in the renal mesangial cells of normal and diabetic rats were compared by using western blot.2 Results. By comparing the normal lung cells to NSCLC cells, it was found that NEAT1 exerts its effect on the Wnt/b-Catenin pathway through inhibiting miR-101-3p. miR-101-3p inactivates a protein, called SOX9, which activates the Wnt/b-Catenin pathway.3 Thus, overexpression of NEAT1 results in increased activity of SOX9.3 In the second study, the renal mesangial cells of diabetic rats displayed an elevation in both NEAT1 and akt/mTOR pathway activity.2 Knockdown of NEAT1 decreased both Akt/mTOR pathway activity and the proliferation of mesangial cells. It could be hypothesized that NEAT1 could contribute to the NSCLC progression and metastasis through activation of the Akt/mTOR pathway.2 Conclusions. NEAT1 could contribute to NSCLC’s drug resistance through activating the Wnt/b-Catenin and akt/mTOR pathway. Currently, the drugs that target these pathways are under trial independently. For example, Ipafricept targets the Wnt/b-Catenin pathway through inhibiting Wnt ligands.1 Also, Temsirolimus targets the akt/mTOR pathway by inhibiting the serine/threonine kinase activity of mTORC1.6 Thus, combining drugs that inhibit the Wnt/b-Catenin and akt/mTOR pathway could be a subject of future trials.
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- Huang S, Xu Y, Ge X, Xu B, Peng W, Jiang X, Shen L, Xia L. Long noncoding RNA NEAT1 accelerates the proliferation and fibrosis in diabetic nephropathy through activating Akt/mTOR signaling pathway. Journal of Cellular Physiology. 2019; 234(7):11200-11207. doi; 10.1002/jcp.27770.
- Kong X, Zhao Y, Li X, Tao Z, Hou M, Ma H. Overexpression of HIF-2α-Dependent NEAT1 Promotes the Progression of Non- Small Cell Lung Cancer through miR-101- 3p/SOX9/Wnt/β-Catenin Signal Pathway. Cellular Physiology and Biochemistry. 2019; 52(3):368-381. doi: 10.33594/000000026.
- Li B, Gu W, Zhu X. NEAT1 mediates paclitaxel-resistance of non-small cell of lung cancer through activation of Akt/mTOR signaling pathway. Journal of Drug Targeting. 2019; 1-23. doi: 10.1080/1061186x.2019.1585437.
- Lo PK, Wolfson B, Zhou Q. Cellular, physiological and pathological aspects of the long non- coding RNA NEAT1. Front Biology. 2016; 11(6); 413-426. doi: 10.1007/s11515-016-1433-z.
- Mabuchi S, Kuroda H, Takahashi R, Sasano T. The PI3K/AKT/mTOR pathway as a therapeutic target in ovarian cancer. Gynecologic Oncology. 2015; 137(1):173-179. doi: 10.1016/j.ygyno.2015.02.003.
- Sun SJ, Lin Q, Ma JX, Shi WW, Yang B, Li F. Long non-coding RNA NEAT1 acts as oncogene in NSCLC by regulating the Wnt signaling pathway. European Review for Medical and Pharmacological Sciences. 2017; 21(3)504-510.