Association of MicroRNA-21 with P53 at Mutant Sites R175H and R248Q, Clinicopathological Features, and Prognosis of NSCLC

Overview

Journal Mol Ther Oncolytics

Publisher Cell Press

Date 2020 Nov 30

PMID 33251333

Citations 8

Authors

Yaodong Zhou

Dongdong Guo

Yixin Zhang

Affiliations

Soon will be listed here.

Abstract

This study aimed to investigate the association of miRNA-21 with mutant p53 expression, prognosis, interaction, and clinicopathological features of non-small cell lung cancer (NSCLC). Tissue specimens from 200 NSCLC patients were collected for qRT-PCR analysis of miR-21 and p53 expression, and p53 mutations were analyzed by Sanger sequencing. NSCLC cell lines were used to determine the effects of miR-21 knockdown on cell viability, cell cycle distribution, and p53 expression. We found that miR-21 expression was upregulated in NSCLC tissues, which was associated with an increase in p53 mRNA levels and with advanced tumor-node-metastasis (TNM) stages and lymph node metastasis. The most common mutant sites of p53 in NSCLC were R175H and R248Q. Moreover, elevated miR-21 and p53 expression levels were associated with shorter overall survival. Knockdown of miR-21 reduced NSCLC cell viability, arrested NSCLC cells at the G-to-G phase of the cell cycle, and downregulated mutant p53 mRNA levels and phosphorylated p53 protein expression in A549 and H1650 cells compared to control cells. miR-21 is associated p53 at mutant sites R175H and R248Q, which seems not to be oncogenic, as it is being reported, since in a normal cell, without a mutated p53, it will probably have a protective role.

Citing Articles

An update on the molecular mechanisms underlying the progression of miR-21 in oral cancer.

Prasad M, Hamsa D, Fareed M, Karobari M World J Surg Oncol. 2025; 23(1):73.

PMID: 40025548 PMC: 11871704. DOI: 10.1186/s12957-025-03732-2.

MicroRNA in lung cancer-a novel potential way for early diagnosis and therapy.

Frydrychowicz M, Kuszel L, Dworacki G, Budna-Tukan J J Appl Genet. 2023; 64(3):459-477.

PMID: 36821071 PMC: 10457410. DOI: 10.1007/s13353-023-00750-2.

Non-Coding RNAs in Airway Diseases: A Brief Overview of Recent Data.

Albano G, Gagliardo R, Montalbano A, Profita M Cancers (Basel). 2023; 15(1).

PMID: 36612051 PMC: 9817765. DOI: 10.3390/cancers15010054.

Emerging noncoding RNAs contained in extracellular vesicles: rising stars as biomarkers in lung cancer liquid biopsy.

Cammarata G, de Miguel-Perez D, Russo A, Peleg A, Dolo V, Rolfo C Ther Adv Med Oncol. 2022; 14:17588359221131229.

PMID: 36353504 PMC: 9638531. DOI: 10.1177/17588359221131229.

Screening for Potential Therapeutic Agents for Non-Small Cell Lung Cancer by Targeting Ferroptosis.

Zhao X, Cui L, Zhang Y, Guo C, Deng L, Wen Z Front Mol Biosci. 2022; 9:917602.

PMID: 36203872 PMC: 9532010. DOI: 10.3389/fmolb.2022.917602.

References

Dai Q, Li N, Zhou X . Increased miR-21a provides metabolic advantages through suppression of FBP1 expression in non-small cell lung cancer cells. Am J Cancer Res. 2017; 7(11):2121-2130. PMC: 5714742. View

Zhang J, Zhang C, Hu L, He Y, Shi Z, Tang S . Abnormal Expression of miR-21 and miR-95 in Cancer Stem-Like Cells is Associated with Radioresistance of Lung Cancer. Cancer Invest. 2015; 33(5):165-71. DOI: 10.3109/07357907.2015.1019676. View

Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M . Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006; 9(3):189-98. DOI: 10.1016/j.ccr.2006.01.025. View

Rufini A, Tucci P, Celardo I, Melino G . Senescence and aging: the critical roles of p53. Oncogene. 2013; 32(43):5129-43. DOI: 10.1038/onc.2012.640. View

Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H . Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res. 2004; 64(11):3753-6. DOI: 10.1158/0008-5472.CAN-04-0637. View

Ha D, Choi H, Chevalier C, Zell K, Wang X, Mazzone P . Survival in patients with metachronous second primary lung cancer. Ann Am Thorac Soc. 2014; 12(1):79-84. DOI: 10.1513/AnnalsATS.201406-261OC. View

Clancy L . Reducing lung cancer and other tobacco-related cancers in Europe: smoking cessation is the key. Oncologist. 2013; 19(1):16-20. PMC: 3903069. DOI: 10.1634/theoncologist.2013-0085. View

Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A . A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. Mol Cell. 2018; 71(1):178-190.e8. DOI: 10.1016/j.molcel.2018.06.012. View

Markou A, Zavridou M, Lianidou E . miRNA-21 as a novel therapeutic target in lung cancer. Lung Cancer (Auckl). 2017; 7:19-27. PMC: 5310696. DOI: 10.2147/LCTT.S60341. View

10.

Dashzeveg N, Taira N, Lu Z, Kimura J, Yoshida K . Palmdelphin, a novel target of p53 with Ser46 phosphorylation, controls cell death in response to DNA damage. Cell Death Dis. 2014; 5:e1221. PMC: 4047856. DOI: 10.1038/cddis.2014.176. View

11.

Lu L, Xu H, Yang P, Xue J, Chen C, Sun Q . Involvement of HIF-1α-regulated miR-21, acting via the Akt/NF-κB pathway, in malignant transformation of HBE cells induced by cigarette smoke extract. Toxicol Lett. 2018; 289:14-21. DOI: 10.1016/j.toxlet.2018.02.027. View

12.

Krasnov G, Puzanov G, Kudryavtseva A, Dmitriev A, Beniaminov A, Kondratieva T . [Differential expression of an ensemble of the key genes involved in cell-cycle regulation in lung cancer]. Mol Biol (Mosk). 2017; 51(5):849-856. DOI: 10.7868/S0026898417050135. View

13.

Dong J, Zhang Z, Gu T, Xu S, Dong L, Li X . The role of microRNA-21 in predicting brain metastases from non-small cell lung cancer. Onco Targets Ther. 2017; 10:185-194. PMC: 5207466. DOI: 10.2147/OTT.S116619. View

14.

Shipman R, Schraml P, Colombi M, Raefle G, Dalquen P, Ludwig C . Frequent TP53 gene alterations (mutation, allelic loss, nuclear accumulation) in primary non-small cell lung cancer. Eur J Cancer. 1996; 32A(2):335-41. DOI: 10.1016/0959-8049(95)00535-8. View

15.

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

16.

Roman-Rosales A, Garcia-Villa E, Herrera L, Gariglio P, Diaz-Chavez J . Mutant p53 gain of function induces HER2 over-expression in cancer cells. BMC Cancer. 2018; 18(1):709. PMC: 6029411. DOI: 10.1186/s12885-018-4613-1. View

17.

Denissenko M, Pao A, Tang M, Pfeifer G . Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996; 274(5286):430-2. DOI: 10.1126/science.274.5286.430. View

18.

Ameres S, Zamore P . Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 2013; 14(8):475-88. DOI: 10.1038/nrm3611. View

19.

Afanasyeva E, Mestdagh P, Kumps C, Vandesompele J, Ehemann V, Theissen J . MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. Cell Death Differ. 2011; 18(6):974-84. PMC: 3131937. DOI: 10.1038/cdd.2010.164. View

20.

Fortunato O, Boeri M, Moro M, Verri C, Mensah M, Conte D . Mir-660 is downregulated in lung cancer patients and its replacement inhibits lung tumorigenesis by targeting MDM2-p53 interaction. Cell Death Dis. 2014; 5:e1564. PMC: 4454158. DOI: 10.1038/cddis.2014.507. View