Type III TGF-β receptor inhibits cell proliferation and migration in salivary glands adenoid cystic carcinoma by suppressing NF-κB signaling

Xu,Dongyang; Li,Duo; Lu,Zhiyong; Dong,Xingli; Wang,Xiaofeng

doi:10.3892/or.2015.4390

Type III TGF-β receptor inhibits cell proliferation and migration in salivary glands adenoid cystic carcinoma by suppressing NF-κB signaling

Authors:
- Dongyang Xu
- Duo Li
- Zhiyong Lu
- Xingli Dong
- Xiaofeng Wang
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Affiliations: Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: November 3, 2015 https://doi.org/10.3892/or.2015.4390
Pages: 267-274

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Abstract

It is known that the TGF-β superfamily receptors act as master regulators of cancer progression. However, alteration and role of type III TGF-β receptor (TβRIII, or betaglycan) as the most abundant of the TGF-β receptor has not been explored in salivary gland adenoid cystic carcinoma (ACC). Here, we reported that tumor biopsies and matched normal human salivary glands from patients with ACC were examined for the expression of TβRIII. The expression of TβRIII protein is significantly decreased in ACC patients based on immunohistochemistry and western blot analysis. In vitro, a transient overexpression of TβRIII markedly induced apoptosis and cell cycle arrest in the G2/M phase, thereby inhibited cell viability and migration of ACC-M cells. Co-immunoprecipitation revealed that TβRIII, scaffolding protein-arrestin2 (β-arrestin2) and IκBα formed a complex. Transient overexpression of TβRIII decreased p-p65 expression and increased IκBα expression, which was abolished by knockdown of β-arrestin2. The present study defines TβRIII as a biomarker exerting antitumor action on ACC progression.Gene therapy of TβRIII may be a powerful new approach for ACC disease.

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1	Tian Z, Li L, Wang L, Hu Y and Li J: Salivary gland neoplasms in oral and maxillofacial regions: A 23-year retrospective study of 6982 cases in an eastern Chinese population. Int J Oral Maxillofac Surg. 39:235–242. 2010. View Article : Google Scholar
2	Li J, Wang BY, Nelson M, Li L, Hu Y, Urken ML and Brandwein-Gensler M: Salivary adenocarcinoma, not otherwise specified: A collection of orphans. Arch Pathol Lab Med. 128:1385–1394. 2004.PubMed/NCBI
3	Spiro RH, Huvos AG and Strong EW: Adenoid cystic carcinoma: Factors influencing survival. Am J Surg. 138:579–583. 1979. View Article : Google Scholar : PubMed/NCBI
4	Zhang CY, Zhao YX, Xia RH, Han J, Wang BS, Tian Z, Wang LZ, Hu YH and Li J: RASSF1A promoter hypermethylation is a strong biomarker of poor survival in patients with salivary adenoid cystic carcinoma in a Chinese population. PLoS One. 9:e1101592014. View Article : Google Scholar : PubMed/NCBI
5	Laurie SA and Licitra L: Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol. 24:2673–2678. 2006. View Article : Google Scholar : PubMed/NCBI
6	Dong M, How T, Kirkbride KC, Gordon KJ, Lee JD, Hempel N, Kelly P, Moeller BJ, Marks JR and Blobe GC: The type III TGF-beta receptor suppresses breast cancer progression. J Clin Invest. 117:206–217. 2007. View Article : Google Scholar
7	Bandyopadhyay A, López-Casillas F, Malik SN, Montiel JL, Mendoza V, Yang J and Sun LZ: Antitumor activity of a recombinant soluble betaglycan in human breast cancer xenograft. Cancer Res. 62:4690–4695. 2002.PubMed/NCBI
8	Finger EC, Turley RS, Dong M, How T, Fields TA and Blobe GC: TbetaRIII suppresses non-small cell lung cancer invasiveness and tumorigenicity. Carcinogenesis. 29:528–535. 2008. View Article : Google Scholar : PubMed/NCBI
9	Hempel N, How T, Cooper SJ, Green TR, Dong M, Copland JA, Wood CG and Blobe GC: Expression of the type III TGF-beta receptor is negatively regulated by TGF-beta. Carcinogenesis. 29:905–912. 2008. View Article : Google Scholar : PubMed/NCBI
10	Turley RS, Finger EC, Hempel N, How T, Fields TA and Blobe GC: The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Res. 67:1090–1098. 2007. View Article : Google Scholar : PubMed/NCBI
11	Sharifi N, Hurt EM, Kawasaki BT and Farrar WL: TGFBR3 loss and consequences in prostate cancer. Prostate. 67:301–311. 2007. View Article : Google Scholar
12	Gordon KJ, Kirkbride KC, How T and Blobe GC: Bone morphogenetic proteins induce pancreatic cancer cell invasiveness through a Smad1-dependent mechanism that involves matrix metalloproteinase-2. Carcinogenesis. 30:238–248. 2009. View Article : Google Scholar :
13	Mythreye K and Blobe GC: The type III TGF-beta receptor regulates epithelial and cancer cell migration through beta-arrestin2-mediated activation of Cdc42. Proc Natl Acad Sci USA. 106:8221–8226. 2009. View Article : Google Scholar : PubMed/NCBI
14	Meng W, Xia Q, Wu L, Chen S, He X, Zhang L, Gao Q and Zhou H: Downregulation of TGF-beta receptor types II and III in oral squamous cell carcinoma and oral carcinoma-associated fibroblasts. BMC Cancer. 11:882011. View Article : Google Scholar : PubMed/NCBI
15	Gatza CE, Holtzhausen A, Kirkbride KC, Morton A, Gatza ML, Datto MB and Blobe GC: Type III TGF-β receptor enhances colon cancer cell migration and anchorage-independent growth. Neoplasia. 13:758–770. 2011. View Article : Google Scholar : PubMed/NCBI
16	Jovanović B, Beeler JS, Pickup MW, Chytil A, Gorska AE, Ashby WJ, Lehmann BD, Zijlstra A, Pietenpol JA and Moses HL: Transforming growth factor beta receptor type III is a tumor promoter in mesenchymal-stem like triple negative breast cancer. Breast Cancer Res. 16:R692014. View Article : Google Scholar
17	Chu WF, Wu DM, Liu W, Wu LJ, Li DZ, Xu DY and Wang XF: Sulforaphane induces G2-M arrest and apoptosis in high metastasis cell line of salivary gland adenoid cystic carcinoma. Oral Oncol. 45:998–1004. 2009. View Article : Google Scholar : PubMed/NCBI
18	Vlantis K, Wullaert A, Sasaki Y, Schmidt-Supprian M, Rajewsky K, Roskams T and Pasparakis M: Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice. J Clin Invest. 121:2781–2793. 2011. View Article : Google Scholar : PubMed/NCBI
19	Zhang J and Peng B: In vitro angiogenesis and expression of nuclear factor kappaB and VEGF in high and low metastasis cell lines of salivary gland adenoid cystic carcinoma. BMC Cancer. 7:952007. View Article : Google Scholar : PubMed/NCBI
20	Lu T, Tian L, Han Y, Vogelbaum M and Stark GR: Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways. Proc Natl Acad Sci USA. 104:4365–4370. 2007. View Article : Google Scholar : PubMed/NCBI
21	Monteleone G, Mann J, Monteleone I, Vavassori P, Bremner R, Fantini M, Del Vecchio Blanco G, Tersigni R, Alessandroni L, Mann D, et al: A failure of transforming growth factor-beta1 negative regulation maintains sustained NF-kappaB activation in gut inflammation. J Biol Chem. 279:3925–3932. 2004. View Article : Google Scholar
22	You HJ, How T and Blobe GC: The type III transforming growth factor-beta receptor negatively regulates nuclear factor kappa B signaling through its interaction with beta-arrestin2. Carcinogenesis. 30:1281–1287. 2009. View Article : Google Scholar : PubMed/NCBI
23	Zheng F, He K, Li X, Zhao D, Sun F, Zhang Y, Nie D, Li X, Chu W, Sun Y, et al: Transient overexpression of TGFBR3 induces apoptosis in human nasopharyngeal carcinoma CNE-2Z cells. Biosci Rep. 33:e000292013. View Article : Google Scholar : PubMed/NCBI
24	Gatza CE, Oh SY and Blobe GC: Roles for the type III TGF-beta receptor in human cancer. Cell Signal. 22:1163–1174. 2010. View Article : Google Scholar : PubMed/NCBI
25	Zanotto-Filho A, Delgado-Cañedo A, Schröder R, Becker M, Klamt F and Moreira JC: The pharmacological NFkappaB inhibitors BAY117082 and MG132 induce cell arrest and apoptosis in leukemia cells through ROS-mitochondria pathway activation. Cancer Lett. 288:192–203. 2010. View Article : Google Scholar
26	Yan X, Shen H, Jiang H, Zhang C, Hu D, Wang J and Wu X: External Qi of Yan Xin Qigong induces G2/M arrest and apop tosis of androgen-independent prostate cancer cells by inhibiting Akt and NF-kappa B pathways. Mol Cell Biochem. 310:227–234. 2008. View Article : Google Scholar
27	Zanotto-Filho A, Braganhol E, Battastini AM and Moreira JC: Proteasome inhibitor MG132 induces selective apoptosis in glioblastoma cells through inhibition of PI3K/Akt and NFkappaB pathways, mitochondrial dysfunction, and activation of p38-JNK1/2 signaling. Invest New Drugs. 30:2252–2262. 2012. View Article : Google Scholar : PubMed/NCBI
28	Zheng M, Ekmekcioglu S, Walch ET, Tang CH and Grimm EA: Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells. Melanoma Res. 14:165–171. 2004. View Article : Google Scholar : PubMed/NCBI
29	Chen W, Kirkbride KC, How T, Nelson CD, Mo J, Frederick JP, Wang XF, Lefkowitz RJ and Blobe GC: Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science. 301:1394–1397. 2003. View Article : Google Scholar : PubMed/NCBI
30	Gao H, Sun Y, Wu Y, Luan B, Wang Y, Qu B and Pei G: Identification of beta-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-kappaB pathways. Mol Cell. 14:303–317. 2004. View Article : Google Scholar : PubMed/NCBI
31	Witherow DS, Garrison TR, Miller WE and Lefkowitz RJ: Beta-arrestin inhibits NF-kappaB activity by means of its interaction with the NF-kappaB inhibitor IkappaBalpha. Proc Natl Acad Sci USA. 101:8603–8607. 2004. View Article : Google Scholar : PubMed/NCBI