MicroRNA‑133a‑3p suppresses malignant behavior of non‑small cell lung cancer cells by negatively regulating ERBB2

Xu,Yanhui; Zhang,Lei; Xia,Lilong; Zhu,Xinhai

doi:10.3892/ol.2021.12718

MicroRNA‑133a‑3p suppresses malignant behavior of non‑small cell lung cancer cells by negatively regulating ERBB2

Authors:
- Yanhui Xu
- Lei Zhang
- Lilong Xia
- Xinhai Zhu
View Affiliations

Affiliations: Department of Thoracic Surgery, Zhejiang Hospital, Hangzhou, Zhejiang 310030, P.R. China
Published online on: April 8, 2021 https://doi.org/10.3892/ol.2021.12718
Article Number: 457

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Non‑small cell lung cancer (NSCLC) has high morbidity and mortality rates worldwide, and tumor metastasis is generally associated with poor prognosis. Chemotherapy resistance aggravates the challenges associated with treating NSCLC. Therefore, identifying effective targets and developing therapies based on these findings could bring novel perspectives for patients with metastatic NSCLC. The expression levels of receptor tyrosine‑protein kinase erbB‑2 (ERBB2) are associated with NSCLC progression. Differential microRNA (miR) expression profiles have been identified in tumors and can be used to identify multiple malignant phenotypes. miR‑133a‑3p expression is dysregulated in a variety of tumors. However, to the best of our knowledge, the association between miR‑133a‑3p and the NSCLC pathogenesis process has not been demonstrated yet. The present study revealed a decrease in miR‑133a‑3p expression in both tissues and cell lines, which was detected using reverse transcription‑quantitative (RT‑q)PCR, and western blotting and RT‑qPCR demonstrated ERBB2 levels were increased at both protein and mRNA levels. Bioinformatics analysis and dual‑luciferase reporter assays demonstrated that ERBB2 was a direct target of miR‑133a‑3p. Furthermore, MTT, wound healing and Transwell assays revealed that overexpression of miR‑133a‑3p suppressed proliferation, invasion and migration of NSCLC cells, respectively, effects that were inhibited following ERBB2 overexpression. In addition, immunofluorescence assays demonstrated that overexpression of ERBB2 upregulated N‑cadherin expression, while E‑cadherin expression was downregulated. In conclusion, the present data demonstrated that miR‑133a‑3p acted as a tumor suppressor by negatively regulating ERBB2 expression. The miR‑133a‑3p/ERBB2 axis may be a potential target for the diagnosis and treatment of NSCLC in the future.

View Figures

View References

1	Duffy SW and Field JK: Mortality reduction with low-dose CT screening for lung cancer. N Engl J Med. 382:572–573. 2020. View Article : Google Scholar : PubMed/NCBI
2	Qi M, Dai D, Liu J, Li Z, Liang P, Wang Y, Cheng L, Zhan Y, An Z, Song Y, et al: AIM2 promotes the development of non-small cell lung cancer by modulating mitochondrial dynamics. Oncogene. 39:2707–2723. 2020. View Article : Google Scholar : PubMed/NCBI
3	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
4	Zhang H, Qian G, Zong D, Fan S, Owonikoko TK, Ramalingam SS and Sun SY: Overcoming acquired resistance of epidermal growth factor receptor-mutant non-small cell lung cancer cells to osimertinib by combining osimertinib with the histone deacetylase inhibitor panobinostat (LBH589). Cancer. 126:2024–2033. 2020. View Article : Google Scholar
5	Morgensztern D, Ng SH, Gao F and Govindan R: Trends in stage distribution for patients with non-small cell lung cancer: A national cancer database survey. J Thorac Oncol. 5:29–33. 2010. View Article : Google Scholar : PubMed/NCBI
6	Du L and Morgensztern D: Chemotherapy for advanced-stage non-small cell lung cancer. Cancer J. 21:366–370. 2015. View Article : Google Scholar : PubMed/NCBI
7	Zhang Q, Zhou L, Guan Y, Cheng Y and Han X: BENC-511, a novel PI3K inhibitor, suppresses metastasis of non-small cell lung cancer cells by modulating β-catenin/ZEB1 regulatory loop. Chem Biol Interact. 294:18–27. 2018. View Article : Google Scholar : PubMed/NCBI
8	Yang ZY, Yang L, Xu CW, Wang XJ and Lei L: An insertion mutation of ERBB2 enhances breast cancer cell growth and confers resistance to lapatinib through AKT signaling pathway. Biol Open. 9:bio0476622020. View Article : Google Scholar : PubMed/NCBI
9	Honkoop H, de Bakker DE, Aharonov A, Kruse F, Shakked A, Nguyen PD, de Heus C, Garric L, Muraro MJ, Shoffner A, et al: Single-cell analysis uncovers that metabolic reprogramming by ErbB2 signaling is essential for cardiomyocyte proliferation in the regenerating heart. Elife. 8:e501632019. View Article : Google Scholar : PubMed/NCBI
10	Albrecht T, Rausch M, Rössler S, Albrecht M, Braun JD, Geissler V, Mehrabi A, Vogel MN, Pathil-Warth A, Mechtersheimer G, et al: HER2 gene (ERBB2) amplification is a rare event in non-liver-fluke associated cholangiocarcinogenesis. BMC Cancer. 19:11912019. View Article : Google Scholar : PubMed/NCBI
11	Menderes G, Bonazzoli E, Bellone S, Black J, Altwerger G, Masserdotti A, Pettinella F, Zammataro L, Buza N, Hui P, et al: SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. Gynecol Oncol. 146:179–186. 2017. View Article : Google Scholar : PubMed/NCBI
12	Ahmed S, Sami A and Xiang J: HER2-directed therapy: Current treatment options for HER2-positive breast cancer. Breast Cancer. 22:101–116. 2015. View Article : Google Scholar : PubMed/NCBI
13	Li L, Jia L and Ding Y: Upregulation of miR-375 inhibits human liver cancer cell growth by modulating cell proliferation and apoptosis via targeting ErbB2. Oncol Lett. 16:3319–3326. 2018.PubMed/NCBI
14	Rimawi MF, Schiff R and Osborne CK: Targeting HER2 for the treatment of breast cancer. Annu Rev Med. 66:111–128. 2015. View Article : Google Scholar : PubMed/NCBI
15	Xiang Z, Huang X, Wang J, Zhang J, Ji J, Yan R, Zhu Z, Cai W and Yu Y: Cross-database analysis reveals sensitive biomarkers for combined therapy for ERBB2⁺ gastric cancer. Front Pharmacol. 9:8612018. View Article : Google Scholar : PubMed/NCBI
16	Wu J, Li S, Ma R, Sharma A, Bai S, Dun B, Cao H, Jing C, She J and Feng J: Tumor profiling of co-regulated receptor tyrosine kinase and chemoresistant genes reveal different targeting options for lung and gastroesophageal cancers. Am J Transl Res. 8:5729–5740. 2016.PubMed/NCBI
17	Liang CH, Shiu LY, Chang LC, Sheu HM and Kuo KW: Solamargine upregulation of Fas, downregulation of HER2, and enhancement of cytotoxicity using epirubicin in NSCLC cells. Mol Nutr Food Res. 51:999–1005. 2007. View Article : Google Scholar : PubMed/NCBI
18	Lu TX and Rothenberg ME: MicroRNA. J Allergy Clin Immunol. 141:1202–1207. 2018. View Article : Google Scholar : PubMed/NCBI
19	Olejniczak M, Kotowska-Zimmer A and Krzyzosiak W: Stress-induced changes in miRNA biogenesis and functioning. Cell Mol Life Sci. 75:177–191. 2018. View Article : Google Scholar : PubMed/NCBI
20	Ohanian M, Humphreys DT, Anderson E, Preiss T and Fatkin D: A heterozygous variant in the human cardiac miR-133 gene, MIR133A2, alters miRNA duplex processing and strand abundance. BMC Genet. 14:182013. View Article : Google Scholar : PubMed/NCBI
21	Zhang X, Li Z, Xuan Z, Xu P, Wang W, Chen Z, Wang S, Sun G, Xu J and Xu Z: Novel role of miR-133a-3p in repressing gastric cancer growth and metastasis via blocking autophagy-mediated glutaminolysis. J Exp Clin Cancer Res. 37:3202018. View Article : Google Scholar : PubMed/NCBI
22	Gao L, Li SH, Tian YX, Zhu QQ, Chen G, Pang YY and Hu XH: Role of downregulated miR-133a-3p expression in bladder cancer: A bioinformatics study. Onco Targets Ther. 10:3667–3683. 2017. View Article : Google Scholar : PubMed/NCBI
23	He B, Lin X, Tian F, Yu W and Qiao B: miR-133a-3p inhibits oral squamous cell carcinoma (OSCC) proliferation and invasion by suppressing COL1A1. J Cell Biochem. 119:338–346. 2018. View Article : Google Scholar : PubMed/NCBI
24	Yang ZQ, Wu CA and Cheng YX: Prognostic value of microRNA-133a expression and its clinicopathologic significance in non-small cell lung cancer: A comprehensive study based on meta-analysis and the TCGA database. Oncol Res Treat. 41:762–768. 2018. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
26	Tian L, Chen M, He Q, Yan Q and Zhai C: MicroRNA-199a-5p suppresses cell proliferation, migration and invasion by targeting ITGA3 in colorectal cancer. Mol Med Rep. 22:2307–2317. 2020. View Article : Google Scholar : PubMed/NCBI
27	Gamerith G, Kocher F, Rudzki J and Pircher A: ASCO 2018 NSCLC highlights-combination therapy is key. Memo. 11:266–271. 2018. View Article : Google Scholar : PubMed/NCBI
28	Tian Y, Sun C, Zhang L and Pan Y: Clinical significance of miRNA-106a in non-small cell lung cancer patients who received cisplatin combined with gemcitabine chemotherapy. Cancer Biol Med. 15:157–164. 2018. View Article : Google Scholar : PubMed/NCBI
29	Hu Y, Liu C and Muyldermans S: Nanobody-based delivery systems for diagnosis and targeted tumor therapy. Front Immunol. 8:14422017. View Article : Google Scholar : PubMed/NCBI
30	McGuire A, Brown JA and Kerin MJ: Metastatic breast cancer: The potential of miRNA for diagnosis and treatment monitoring. Cancer Metastasis Rev. 34:145–155. 2015. View Article : Google Scholar : PubMed/NCBI
31	Shin VY and Chu KM: miRNA as potential biomarkers and therapeutic targets for gastric cancer. World J Gastroenterol. 20:10432–10439. 2014. View Article : Google Scholar : PubMed/NCBI
32	Takahashi RU, Prieto-Vila M, Kohama I and Ochiya T: Development of miRNA-based therapeutic approaches for cancer patients. Cancer Sci. 110:1140–1147. 2019. View Article : Google Scholar : PubMed/NCBI
33	Shi W, Tang T, Li X, Deng S, Li R, Wang Y, Wang Y, Xia T, Zhang Y, Zen K, et al: Methylation-mediated silencing of miR-133a-3p promotes breast cancer cell migration and stemness via miR-133a-3p/MAML1/DNMT3A positive feedback loop. J Exp Clin Cancer Res. 38:4292019. View Article : Google Scholar : PubMed/NCBI
34	Li JP, Zhang HM, Liu MJ, Xiang Y, Li H, Huang F, Li HH, Dai ZT, Gu CJ, Liao XH and Zhang TC: miR-133a-3p/FOXP3 axis regulates cell proliferation and autophagy in gastric cancer. J Cell Biochem. 121:3392–3405. 2020. View Article : Google Scholar : PubMed/NCBI
35	Byeon S, Lee B, Park WY, Choi YL, Jung HA, Sun JM, Ahn JS, Ahn MJ, Park K and Lee SH: Benefit of targeted DNA sequencing in advanced non-small-cell lung cancer patients without EGFR and ALK alterations on conventional tests. Clin Lung Cancer. 21:e182–e190. 2020. View Article : Google Scholar
36	Liberelle M, Jonckheere N, Melnyk P, Van Seuningen I and Lebègue N: EGF-containing membrane-bound mucins: A hidden ErbB2 targeting pathway? J Med Chem. 63:5074–5088. 2020. View Article : Google Scholar : PubMed/NCBI
37	Voelker R: Another targeted therapy for ERBB2-positive breast cancer. JAMA. 323:4082020. View Article : Google Scholar
38	Spencer KS, Graus-Porta D, Leng J, Hynes NE and Klemke RL: ErbB2 is necessary for induction of carcinoma cell invasion by ErbB family receptor tyrosine kinases. J Cell Biol. 148:385–397. 2000. View Article : Google Scholar : PubMed/NCBI
39	Jung DH, Bae YJ, Kim JH, Shin YK and Jeung HC: HER2 regulates cancer stem cell activities via the Wnt signaling pathway in gastric cancer cells. Oncology. 97:311–318. 2019. View Article : Google Scholar : PubMed/NCBI