Identification of ITGB4 as a novel tumor promoting gene in lung adenocarcinoma (LUAD)

Lu,Xuan; Ma,Sai; Li,Ying; Pan,Yunzhi; Kang,Ningning

doi:10.3892/or.2023.8689

Identification of ITGB4 as a novel tumor promoting gene in lung adenocarcinoma (LUAD)

Authors:
- Xuan Lu
- Sai Ma
- Ying Li
- Yunzhi Pan
- Ningning Kang
View Affiliations

Affiliations: School of Life Sciences, Hefei Normal University, Hefei, Anhui 230000, P.R. China, Department of Central Laboratory, The Affiliated Suzhou Hospital of Nanjing Medical University, Gusu School, Nanjing Medical University, Suzhou, Jiangsu 215000, P.R. China, Department of Pharmacy, The Affiliated Infectious Diseases Hospital of Soochow University, The Fifth People's Hospital of Suzhou, Suzhou, Jiangsu 215000, P.R. China, Department of Thoracic Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
Published online on: December 20, 2023 https://doi.org/10.3892/or.2023.8689
Article Number: 30
Copyright: © Lu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

As the most frequently diagnosed cancer, lung cancer (LC) is the most common cause of cancer‑related death worldwide. In total, ~85% of malignant lung tumors belong to non‑small cell LC, of which ~50% are lung adenocarcinoma (LUAD). Integrin subunit β4 (ITGB4) is upregulated in lung glandular cancer and elevated ITGB4 levels predict an adverse clinical outcome. However, the biological function of ITGB4 in promoting LUAD progression remains unclear. In the present study, the upregulation of ITGB4 in LUAD tissue samples was demonstrated. To understand the biological role of ITGB4, ITGB4 expression was knocked down in A549 and PC9 cells through transfection with specific small interfering RNAs. The results demonstrated that the downregulation of ITGB4 attenuated A549 and PC9 cell proliferation, promoted cell apoptosis and inhibited colony formation, cell migration and cell invasion. To understand the mechanism of ITGB4, high throughput sequencing was performed using ITGB4‑knocked down A549 cells, followed by bioinformatics analysis. It was found that the genes upregulated by ITGB4 were significantly enriched in metabolism and related pathways, and the genes downregulated by ITGB4 were enriched in cell cycle and related pathways. In conclusion, the findings of the present study highlighted the oncogenic function of ITGB4 in LUAD and uncovered potential mechanisms fundamental to the progression of the disease.

View Figures

View References

1	Martin P and Leighl NB: Review of the use of pretest probability for molecular testing in non-small cell lung cancer and overview of new mutations that may affect clinical practice. Ther Adv Med Oncol. 9:405–414. 2017. View Article : Google Scholar : PubMed/NCBI
2	Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI
3	Dong HX, Wang R, Jin XY, Zeng J and Pan J: LncRNA DGCR5 promotes lung adenocarcinoma (LUAD) progression via inhibiting hsa-mir-22-3p. J Cell Physiol. 233:4126–4136. 2018. View Article : Google Scholar : PubMed/NCBI
4	Herbst RS, Morgensztern D and Boshoff C: The biology and management of non-small cell lung cancer. Nature. 553:446–454. 2018. View Article : Google Scholar : PubMed/NCBI
5	Jan YH, Lai TC, Yang CJ, Huang MS and Hsiao M: A co-expressed gene status of adenylate kinase 1/4 reveals prognostic gene signature associated with prognosis and sensitivity to EGFR targeted therapy in lung adenocarcinoma. Sci Rep. 9:123292019. View Article : Google Scholar : PubMed/NCBI
6	Bianconi D, Unseld M and Prager GW: Integrins in the Spotlight of Cancer. Int J Mol Sci. 17:20372016. View Article : Google Scholar : PubMed/NCBI
7	Slack-Davis JK and Parsons JT: Emerging views of integrin signaling: Implications for prostate cancer. J Cell Biochem. 91:41–46. 2004. View Article : Google Scholar : PubMed/NCBI
8	Brakebusch C, Bouvard D, Stanchi F, Saki T and Fassler R: Integrins in invasive growth. J Clin Invest. 109:999–1006. 2002. View Article : Google Scholar : PubMed/NCBI
9	Hynes RO: Integrins-Versatility, modulation, and signaling in cell adhesion. Cell. 69:11–25. 1992. View Article : Google Scholar : PubMed/NCBI
10	Wang L, Dong Z, Zhang Y and Miao J: The roles of integrin β4 in vascular endothelial cells. J Cell Physiol. 227:474–478. 2012. View Article : Google Scholar : PubMed/NCBI
11	Ma B, Zhang L, Zou YJ, He R, Wu Q, Han C and Zhang B: Reciprocal regulation of integrin β4 and KLF4 promotes gliomagenesis through maintaining cancer stem cell traits. J Exp Clin Cancer Res. 38:232019. View Article : Google Scholar : PubMed/NCBI
12	Li XL, Liu L, Li DD, He YP, Guo LH, Sun LP, Liu LN, Xu HX and Zhang XP: Integrin β 4 promotes cell invasion and epithelial-mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma. Sci Rep. 7:404642017. View Article : Google Scholar : PubMed/NCBI
13	Trusolino L, Bertotti A and Comoglio PM: A signaling adapter function for alpha6beta4 integrin in the control of HGF-dependent invasive growth. Cell. 107:643–654. 2001. View Article : Google Scholar : PubMed/NCBI
14	Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, et al: Tumour exosome integrins determine organotropic metastasis. Nature. 527:329–335. 2015. View Article : Google Scholar : PubMed/NCBI
15	Wu P, Wang Y, Wu Y, Jia Z, Song Y and Liang N: Expression and prognostic analyses of ITGA11, ITGB4 and ITGB8 in human non-small cell lung cancer. Peerj. 7:e82992019. View Article : Google Scholar : PubMed/NCBI
16	Smyth GK, Michaud J and Scott HS: Use of within-array replicate spots for assessing differential expression in microarray experiments. Bioinformatics. 21:2067–2075. 2005. View Article : Google Scholar : PubMed/NCBI
17	Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BVSK and Varambally S: UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 19:649–658. 2017. View Article : Google Scholar : PubMed/NCBI
18	Rhodes DR, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs BB, Barrette TR, Anstet MJ, Kincead-Beal C, Kulkarni P, et al: Oncomine 3.0: Genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 9:166–180. 2007. View Article : Google Scholar : PubMed/NCBI
19	Huang C, Liu J, Xiong B, Yonemura Y and Yang X: Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer. Gene. 685:202–210. 2019. View Article : Google Scholar : PubMed/NCBI
20	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
21	Qin Z, Xiang C, Zhong F, Liu Y, Dong Q, Li K, Shi W, Ding C, Qin L and He F: Transketolase (TKT) activity and nuclear localization promote hepatocellular carcinoma in a metabolic and a non-metabolic manner. J Exp Clin Cancer Res. 38:1542019. View Article : Google Scholar : PubMed/NCBI
22	Tagliabue E, Ghirelli C, Squicciarini P, Aiello P, Colnaghi MI and Menard S: Prognostic value of alpha 6 beta 4 integrin expression in breast carcinomas is affected by laminin production from tumor cells. Clin Cancer Res. 4:407–410. 1998.PubMed/NCBI
23	Grossman HB, Lee C, Bromberg J and Liebert M: Expression of the alpha6beta4 integrin provides prognostic information in bladder cancer. Oncol Rep. 7:13–16. 2000.PubMed/NCBI
24	Gan L, Meng J, Xu M, Liu M, Qi Y, Tan C, Wang Y, Zhang P, Weng W, Sheng W, et al: Extracellular matrix protein 1 promotes cell metastasis and glucose metabolism by inducing integrin β4/FAK/SOX2/HIF-1α signaling pathway in gastric cancer. Oncogene. 37:744–755. 2018. View Article : Google Scholar : PubMed/NCBI
25	Diaz LK, Cristofanilli M, Zhou X, Welch KL, Smith TL, Yang Y, Sneige N, Sahin AA and Gilcrease MZ: beta4 integrin subunit gene expression correlates with tumor size and nuclear grade in early breast cancer. Mod Pathol. 18:1165–1175. 2005. View Article : Google Scholar : PubMed/NCBI
26	Jiang X, Wang J, Wang M, Xuan M, Han S, Li C, Li M, Sun XF, Yu W and Zhao Z: ITGB4 as a novel serum diagnosis biomarker and potential therapeutic target for colorectal cancer. Cancer Med. 10:6823–6834. 2021. View Article : Google Scholar : PubMed/NCBI
27	Meng X, Liu P, Wu Y, Liu X, Huang Y, Yu B, Han J, Jin H and Tan X: Integrin beta 4 (ITGB4) and its tyrosine-1510 phosphorylation promote pancreatic tumorigenesis and regulate the MEK1-ERK1/2 signaling pathway. Bosn J Basic Med Sci. 20:106–116. 2020.PubMed/NCBI
28	Wilkinson EJ, Woodworth AM, Parker M, Phillips JL, Malley RC, Dickinson JL and Holloway AF: Epigenetic regulation of the ITGB4 gene in prostate cancer. Exp Cell Res. 392:1120552020. View Article : Google Scholar : PubMed/NCBI
29	Ruan S, Lin M, Zhu Y, Lum L, Thakur A, Jin R, Shao W, Zhang Y, Hu Y, Huang S, et al: Integrin β4-Targeted cancer immunotherapies inhibit tumor growth and decrease metastasis. Cancer Res. 80:771–783. 2020. View Article : Google Scholar : PubMed/NCBI
30	Sena LA and Chandel NS: Physiological roles of mitochondrial reactive oxygen species. Mol Cell. 48:158–167. 2012. View Article : Google Scholar : PubMed/NCBI
31	Kubli DA and Gustafsson AB: Mitochondria and mitophagy: The yin and yang of cell death control. Circ Res. 111:1208–1221. 2012. View Article : Google Scholar : PubMed/NCBI
32	Zhuang Z, Zhou R, Xu X, Tian T, Liu Y, Liu Y, Lian P, Wang J and Xu K: Clinical significance of integrin αvβ6 expression effects on gastric carcinoma invasiveness and progression via cancer-associated fibroblasts. Med Oncol. 30:5802013. View Article : Google Scholar : PubMed/NCBI