Silencing of aquaporin 5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Zhang,Lin; Lu,Jia; Zhou,Hongyan; Du,Zhenwu; Zhang,Guizhen

doi:10.3892/ijo.2018.4326

Silencing of aquaporin 5 inhibits the growth of A549 lung cancer cells in vitro and in vivo

Authors:
- Lin Zhang
- Jia Lu
- Hongyan Zhou
- Zhenwu Du
- Guizhen Zhang
View Affiliations

Affiliations: Central Laboratory, The Second Hospital of Jilin University, Changchun, Jilin 130041, P.R. China, Department of Ophthalmology, China-Japan Union Hospital, Jilin University, Changchun, Jilin 130033, P.R. China
Published online on: March 16, 2018 https://doi.org/10.3892/ijo.2018.4326
Pages: 1643-1650

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

The water channel protein aquaporin 5 (AQP5) is highly expressed in numerous tumors. However, its expression pattern and functions in lung cancer in humans remain unknown. In the present study, the role of AQP5 in the development of lung malignancies was examined. A short hairpin RNA construct targeting AQP5 mRNA was transfected into A549 cells to generate a lung cancer cell line in which AQP5 expression was stably silenced. In vitro and in vivo experiments were then performed to establish the effects of AQP5 on A549 cell apoptosis, proliferation and cell cycle progression. The results demonstrated that AQP5 silencing significantly inhibited the proliferation and promoted the apoptosis of A549 lung cancer cells in vitro and in vivo. In addition, it resulted in decreased activation of the extracellular signal-regulated kinase 1/2 signaling pathway in A549 cells, and reduced levels of the downstream proteins c‑Fos and phosphorylated cAMP response element-binding protein. Furthermore, inhibition of AQP5 expression effectively reduced the tumorigenicity of A549 cells in vivo. In conclusion, silencing of AQP5 suppressed the growth of A549 cells in vitro and in vivo, suggesting that it may serve as a therapeutic target in lung cancer.

View Figures

View References

1	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2016. CA Cancer J Clin. 66:7–30. 2016. View Article : Google Scholar : PubMed/NCBI
3	Jin C, Zhang G, Zhang Y, Hua P, Song G, Sun M, Li X, Tong T, Li B and Zhang X: Isoalantolactone induces intrinsic apoptosis through p53 signaling pathway in human lung squamous carcinoma cells. PLoS One. 12:e01817312017. View Article : Google Scholar : PubMed/NCBI
4	He F, Du T, Jiang Q and Zhang Y: Synergistic effect of Notch-3-specific inhibition and paclitaxel in non-small cell lung cancer (NSCLC) cells via activation of the intrinsic apoptosis pathway. Med Sci Monit. 23:3760–3769. 2017. View Article : Google Scholar : PubMed/NCBI
5	Ridge CA, McErlean AM and Ginsberg MS: Epidemiology of lung cancer. Semin Intervent Radiol. 30:93–98. 2013. View Article : Google Scholar :
6	Wang L, Li R, Che K, Liu Z, Xiang S, Li M and Yu Y: Enhanced antitumor effect on intrapulmonary tumors of docetaxel lung-targeted liposomes in a rabbit model of VX2 orthotopic lung cancer. Sci Rep. 7:100692017. View Article : Google Scholar : PubMed/NCBI
7	Howington JA, Blum MG, Chang AC, Balekian AA and Murthy SC: Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 143:e278S–e313S. 2013. View Article : Google Scholar : PubMed/NCBI
8	Collisson EA, Campbell JD, Brooks AN, Berger AH, Lee W, Chmielecki J, Beer DG, Cope L, Creighton CJ, Danilova L, et al Cancer Genome Atlas Research Network: Comprehensive molecular profiling of lung adenocarcinoma. Nature. 511:543–550. 2014. View Article : Google Scholar
9	Wang M, Lin T, Wang Y, Gao S, Yang Z, Hong X and Chen G: CXCL12 suppresses cisplatin-induced apoptosis through activation of JAK2/STAT3 signaling in human non-small-cell lung cancer cells. Onco Targets Ther. 10:3215–3224. 2017. View Article : Google Scholar : PubMed/NCBI
10	Agre P and Kozono D: Aquaporin water channels: Molecular mechanisms for human diseases. FEBS Lett. 555:72–78. 2003. View Article : Google Scholar : PubMed/NCBI
11	Shen Q, Lin W, Luo H, Zhao C, Cheng H, Jiang W and Zhu X: Differential expression of aquaporins in cervical precursor lesions and invasive cervical cancer. Reprod Sci. 23:1551–1558. 2016. View Article : Google Scholar : PubMed/NCBI
12	Agre P: The aquaporin water channels. Proc Am Thorac Soc. 3:5–13. 2006. View Article : Google Scholar : PubMed/NCBI
13	Verkman AS: More than just water channels: Unexpected cellular roles of aquaporins. J Cell Sci. 118:3225–3232. 2005. View Article : Google Scholar : PubMed/NCBI
14	Chae YK, Woo J, Kim MJ, Kang SK, Kim MS, Lee J, Lee SK, Gong G, Kim YH, Soria JC, et al: Expression of aquaporin 5 (AQP5) promotes tumor invasion in human non small cell lung cancer. PLoS One. 3:e21622008. View Article : Google Scholar : PubMed/NCBI
15	Jung HJ, Park JY, Jeon HS and Kwon TH: Aquaporin-5: A marker protein for proliferation and migration of human breast cancer cells. PLoS One. 6:e284922011. View Article : Google Scholar : PubMed/NCBI
16	Lee SJ, Kang BW, Kim JG, Jung JH, Lee J, Kim WW, Park HY, Jeong JH, Jeong JY, Park JY, et al: AQP5 variants affect tumoral expression of AQP5 and survival in patients with early breast cancer. Oncology. 92:153–160. 2017. View Article : Google Scholar
17	Yang J, Zhang JN, Chen WL, Wang GS, Mao Q, Li SQ, Xiong WH, Lin YY, Ge JW, Li XX, et al: Effects of AQP5 gene silencing on proliferation, migration and apoptosis of human glioma cells through regulating EGFR/ERK/p38 MAPK signaling pathway. Oncotarget. 8:38444–38455. 2017.PubMed/NCBI
18	Xin LB, Jiang XX, Ye XL, Wu RJ, Xu KH, Ma JY and Lin J: AQP5 gene silencing inhibits proliferation and migration of ectopic endometrial glandular epithelial cells in endometriosis. Zhejiang Da Xue Xue Bao Yi Xue Ban. 44:285–292. 2015.In Chinese. PubMed/NCBI
19	Sugihara I, Yoshida M, Shigenobu T, Takagi H, Maruyama K, Takeuchi N, Toda M, Inoue M and Nakada H: Different progression of tumor xenografts between mucin-producing and mucin-non-producing mammary adenocarcinoma-bearing mice. Cancer Res. 66:6175–6182. 2006. View Article : Google Scholar : PubMed/NCBI
20	Guo K and Jin F: NFAT5 promotes proliferation and migration of lung adenocarcinoma cells in part through regulating AQP5 expression. Biochem Biophys Res Commun. 465:644–649. 2015. View Article : Google Scholar : PubMed/NCBI
21	Direito I, Madeira A, Brito MA and Soveral G: Aquaporin-5: From structure to function and dysfunction in cancer. Cell Mol Life Sci. 73:1623–1640. 2016. View Article : Google Scholar : PubMed/NCBI
22	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
23	Verkman AS, Hara-Chikuma M and Papadopoulos MC: Aquaporins - new players in cancer biology. J Mol Med (Berl). 86:523–529. 2008. View Article : Google Scholar
24	Yang JH, Shi YF, Cheng Q and Deng L: Expression and localization of aquaporin-5 in the epithelial ovarian tumors. Gynecol Oncol. 100:294–299. 2006. View Article : Google Scholar
25	Zhang T, Zhao C, Chen D and Zhou Z: Overexpression of AQP5 in cervical cancer: Correlation with clinicopathological features and prognosis. Med Oncol. 29:1998–2004. 2012. View Article : Google Scholar
26	Shi X, Wu S, Yang Y, Tang L, Wang Y, Dong J, Lü B, Jiang G and Zhao W: AQP5 silencing suppresses p38 MAPK signaling and improves drug resistance in colon cancer cells. Tumour Biol. 35:7035–7045. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yan C, Zhu Y, Zhang X, Chen X, Zheng W and Yang J: Downregulated aquaporin 5 inhibits proliferation and migration of human epithelial ovarian cancer 3AO cells. J Ovarian Res. 7:782014. View Article : Google Scholar
28	Huang YH, Zhou XY, Wang HM, Xu H, Chen J and Lv NH: Aquaporin 5 promotes the proliferation and migration of human gastric carcinoma cells. Tumour Biol. 34:1743–1751. 2013. View Article : Google Scholar : PubMed/NCBI
29	Simpson DJ, Fryer AA, Grossman AB, Wass JA, Pfeifer M, Kros JM, Clayton RN and Farrell WE: Cyclin D1 (CCND1) genotype is associated with tumour grade in sporadic pituitary adenomas. Carcinogenesis. 22:1801–1807. 2001. View Article : Google Scholar : PubMed/NCBI
30	Qi S, Song Y, Peng Y, Wang H, Long H, Yu X, Li Z, Fang L, Wu A, Luo W, et al: ZEB2 mediates multiple pathways regulating cell proliferation, migration, invasion, and apoptosis in glioma. PLoS One. 7:e388422012. View Article : Google Scholar : PubMed/NCBI
31	Zarnescu O, Brehar FM, Chivu M and Ciurea AV: Immunohistochemical localization of caspase-3, caspase-9 and Bax in U87 glioblastoma xenografts. J Mol Histol. 39:561–569. 2008. View Article : Google Scholar : PubMed/NCBI
32	Bhattacharjee M, Acharya S, Ghosh A, Sarkar P, Chatterjee S, Kumar P and Chaudhuri S: Bax and Bid act in synergy to bring about T11TS-mediated glioma apoptosis via the release of mitochondrial cytochrome c and subsequent caspase activation. Int Immunol. 20:1489–1505. 2008. View Article : Google Scholar : PubMed/NCBI
33	Guo Z, Chen Q, Liu B, Tian D, Zhang S and Li M: LRIG1 enhances chemosensitivity by modulating BCL-2 expression and receptor tyrosine kinase signaling in glioma cells. Yonsei Med J. 55:1196–1205. 2014. View Article : Google Scholar : PubMed/NCBI
34	McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar
35	Oh SE and Mouradian MM: Cytoprotective mechanisms of DJ-1 against oxidative stress through modulating ERK1/2 and ASK1 signal transduction. Redox Biol. 14:211–217. 2018. View Article : Google Scholar
36	Zhang Z, Chen Z, Song Y, Zhang P, Hu J and Bai C: Expression of aquaporin 5 increases proliferation and metastasis potential of lung cancer. J Pathol. 221:210–220. 2010. View Article : Google Scholar : PubMed/NCBI
37	Niu C, Xiao F, Yuan K, Hu X, Lin W, Ma R, Zhang X and Huang Z: Nardosinone suppresses RANKL-induced osteoclastogenesis and attenuates lipopolysaccharide-induced alveolar bone resorption. Front Pharmacol. 8:6262017. View Article : Google Scholar : PubMed/NCBI