Hypoxia‑induced galectin‑3 enhances RhoA function to activate the motility of tumor cells in non‑small cell lung cancer

Kataoka,Yoko; Ohshio,Yasuhiko; Teramoto,Koji; Igarashi,Tomoyuki; Asai,Tohru; Hanaoka,Jun

doi:10.3892/or.2018.6915

Hypoxia‑induced galectin‑3 enhances RhoA function to activate the motility of tumor cells in non‑small cell lung cancer

Authors:
- Yoko Kataoka
- Yasuhiko Ohshio
- Koji Teramoto
- Tomoyuki Igarashi
- Tohru Asai
- Jun Hanaoka
View Affiliations

Affiliations: Department of Surgery, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan, Department of Medical Oncology, Shiga University of Medical Science, Otsu, Shiga 520‑2192, Japan
Published online on: December 7, 2018 https://doi.org/10.3892/or.2018.6915
Pages: 853-862
Copyright: © Kataoka 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

Galectin‑3 plays crucial roles in tumor progression. However, in non‑small cell lung cancer (NSCLC), it remains unclear whether the hypoxic tumor microenvironment enhances galectin‑3‑induced cell motility. We investigated galectin‑3 expression in NSCLC cells under hypoxia, and the possible molecular mechanisms by which galectin‑3 influences tumor aggressiveness. Galectin‑3 levels in NSCLC cell lines under hypoxia were assessed using reverse transcription PCR and western blotting. To clarify the role of endogenous galectin‑3, the effect of galectin‑3 knockdown in NSCLC cells was investigated using scratch and invasion assays. The expression and clinicopathological significance of galectin‑3 in 57 patients with pN0M0 invasive pulmonary adenocarcinoma were investigated by immunohistochemistry. Both mRNA and protein levels of galectin‑3 in the NSCLC cell lines A549 and LK‑2 were upregulated by hypoxia. As revealed by scratch and invasion assays, the cell migratory and invasive activities were significantly increased under hypoxia, but were reduced by galectin‑3 knockdown. Notably, addition of galectin‑3 to the media did not improve the cell motility impaired by galectin‑3 knockdown. To clarify the role of endogenous galectin‑3 in the enhancement of tumor cell motility under hypoxia, we focused on the function of RhoA. RhoA level in the plasma membrane, but not in the cytoplasm, was increased under hypoxia and decreased by galectin‑3 knockdown. RhoA activity was significantly enhanced under hypoxia and effectively inhibited by galectin‑3 knockdown. In patients with pN0M0 invasive pulmonary adenocarcinoma, higher galectin‑3 expression on tumor cells was significantly associated with tumor cell invasion into microvessels and tumor recurrence after surgery. These data demonstrate that in NSCLC cells under hypoxia, upregulated galectin‑3 levels increase the localization of RhoA to the plasma membrane, thus enhancing RhoA activity, which is associated with aggressive cell motility. In pN0M0 invasive pulmonary adenocarcinoma, galectin‑3 is a potential biomarker for predicting tumor recurrence after radical surgery.

View Figures

View References

1	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2015. CA Cancer J Clin. 65:5–29. 2015. View Article : Google Scholar : PubMed/NCBI
2	Reck M and Rabe KF: Precision diagnosis and treatment for advanced non-small-cell lung cancer. N Engl J Med. 377:849–861. 2017. View Article : Google Scholar : PubMed/NCBI
3	Goldstraw P, Chansky K, Crowley J, Rami-Porta R, Asamura H, Eberhardt WE, Nicholson AG, Groome P, Mitchell A, Bolejack V, et al: The IASLC lung cancer staging project: Proposals for revision of the TNM stage groupings in the forthcoming (Eighth) edition of the TNM classification for lung cancer. J Thorac Oncol. 11:39–51. 2016. View Article : Google Scholar : PubMed/NCBI
4	Ahmed H and AlSadek DM: Galectin-3 as a potential target to prevent cancer metastasis. Clin Med Insights Oncol. 9:113–121. 2015. View Article : Google Scholar : PubMed/NCBI
5	Cardoso AC, Andrade LN, Bustos SO and Chammas R: Galectin-3 determines tumor cell adaptive strategies in stressed tumor microenvironments. Front Oncol. 6:1272016. View Article : Google Scholar : PubMed/NCBI
6	Chung LY, Tang SJ, Wu YC, Sun GH, Liu HY and Sun KH: Galectin-3 augments tumor initiating property and tumorigenicity of lung cancer through interaction with β-catenin. Oncotarget. 6:4936–4952. 2015. View Article : Google Scholar : PubMed/NCBI
7	Semenza GL: Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 33:207–214. 2012. View Article : Google Scholar : PubMed/NCBI
8	Zeng Y, Danielson KG, Albert TJ, Shapiro IM and Risbud MV: HIF-1 alpha is a regulator of galectin-3 expression in the intervertebral disc. J Bone Miner Res. 22:1851–1861. 2007. View Article : Google Scholar : PubMed/NCBI
9	de Oliveira JT, Ribeiro C, Barros R, Gomes C, de Matos AJ, Reis CA, Rutteman GR and Gärtner F: Hypoxia up-regulates galectin-3 in mammary tumor progression and metastasis. PLoS One. 10:e01344582015. View Article : Google Scholar : PubMed/NCBI
10	Zheng J, Lu W, Wang C, Xing Y, Chen X and Ai Z: Galectin-3 induced by hypoxia promotes cell migration in thyroid cancer cells. Oncotarget. 8:101475–101488. 2017. View Article : Google Scholar : PubMed/NCBI
11	Ikemori RY, Machado CM, Furuzawa KM, Nonogaki S, Osinaga E, Umezawa K, de Carvalho M, Verinaud L and Chammas R: Galectin-3 up-regulation in hypoxic and nutrient deprived microenvironments promotes cell survival. PLoS One. 9:e1115922014. View Article : Google Scholar : PubMed/NCBI
12	Hetmanski JH, Schwartz JM and Caswell PT: Modelling GTPase dynamics to understand RhoA-driven cancer cell invasion. Biochem Soc Trans. 44:1695–1700. 2016. View Article : Google Scholar : PubMed/NCBI
13	Brew CT, Aronchik I, Kosco K, McCammon J, Bjeldanes LF and Firestone GL: Indole-3-carbinol inhibits MDA-MB-231 breast cancer cell motility and induces stress fibers and focal adhesion formation by activation of Rho kinase activity. Int J Cancer. 124:2294–2302. 2009. View Article : Google Scholar : PubMed/NCBI
14	Gao X, Balan V, Tai G and Raz A: Galectin-3 induces cell migration via a calcium-sensitive MAPK/ERK1/2 pathway. Oncotarget. 5:2077–2084. 2014. View Article : Google Scholar : PubMed/NCBI
15	Serizawa N, Tian J, Fukada H, Baghy K, Scott F, Chen X, Kiss Z, Olson K, Hsu D, Liu FT, et al: Galectin 3 regulates HCC cell invasion by RhoA and MLCK activation. Lab Invest. 95:1145–1156. 2015. View Article : Google Scholar : PubMed/NCBI
16	Dumont P, Berton A, Nagy N, Sandras F, Tinton S, Demetter P, Mascart F, Allaoui A, Decaestecker C and Salmon I: Expression of galectin-3 in the tumor immune response in colon cancer. Lab Invest. 88:896–906. 2008. View Article : Google Scholar : PubMed/NCBI
17	Gaida MM, Bach ST, Günther F, Baseras B, Tschaharganeh DF, Welsch T, Felix K, Bergmann F, Hänsch GM and Wente MN: Expression of galectin-3 in pancreatic ductal adenocarcinoma. Pathol Oncol Res. 18:299–307. 2012. View Article : Google Scholar : PubMed/NCBI
18	Garcia-Mata R, Boulter E and Burridge K: The ‘invisible hand’: Regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol. 12:493–504. 2011. View Article : Google Scholar : PubMed/NCBI
19	Shalom-Feuerstein R, Plowman SJ, Rotblat B, Ariotti N, Tian T, Hancock JF and Kloog Y: K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3. Cancer Res. 68:6608–6616. 2008. View Article : Google Scholar : PubMed/NCBI
20	Song S, Ji B, Ramachandran V, Wang H, Hafley M, Logsdon C and Bresalier RS: Overexpressed galectin-3 in pancreatic cancer induces cell proliferation and invasion by binding Ras and activating Ras signaling. PLoS One. 7:e426992012. View Article : Google Scholar : PubMed/NCBI
21	Shimamura T, Sakamoto M, Ino Y, Shimada J, Kosuge T, Sato Y, Tanaka K, Sekihara H and Hirohashi S: Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas. Clin Cancer Res. 8:2570–2575. 2002.PubMed/NCBI
22	Prieto VG, Mourad-Zeidan AA, Melnikova V, Johnson MM, Lopez A, Diwan AH, Lazar AJ, Shen SS, Zhang PS, Reed JA, et al: Galectin-3 expression is associated with tumor progression and pattern of sun exposure in melanoma. Clin Cancer Res. 12:6709–6715. 2006. View Article : Google Scholar : PubMed/NCBI
23	Piantelli M, Iacobelli S, Almadori G, Iezzi M, Tinari N, Natoli C, Cadoni G, Lauriola L and Renalletti FO: Lack of expression of galectin-3 is associated with a poor outcome in node-negative patients with laryngeal squamous-cell carcinoma. J Clin Oncol. 20:3850–3856. 2002. View Article : Google Scholar : PubMed/NCBI
24	Merseburger AS, Kramer MW, Hennenlotter J, Serth J, Kruck S, Gracia A, Stenzl A and Kuczyk MA: Loss of galectin-3 expression correlates with clear cell renal carcinoma progression and reduced survival. World J Urol. 26:637–642. 2008. View Article : Google Scholar : PubMed/NCBI
25	Mathieu A, Saal I, Vuckovic A, Ransy V, Vereerstraten P, Kaltner H, Gabius HJ, Kiss R, Decaestecker C, Salmon I and Remmelink M: Nuclear galectin-3 exprXession is an independent predictive factor of recurrence for adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol. 18:1264–1271. 2005. View Article : Google Scholar : PubMed/NCBI
26	Szöke T, Kayser K, Trojan I, Kayser G, Furak J, Tiszlavicz L, Baumhäkel JD and Gabius HJ: The role of microvascularization and growth/adhesion-regulatory lectins in the prognosis of non-small cell lung cancer in stage II. Eur J Cardiothorac Surg. 31:783–787. 2007. View Article : Google Scholar : PubMed/NCBI
27	Kosacka M, Piesiak P, Kowal A, Gołecki M and Jankowska R: Galectin-3 and cyclin D1 expression in non-small cell lung cancer. J Exp Clin Cancer Res. 30:1012011. View Article : Google Scholar : PubMed/NCBI