Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Tanaka,Takuya; Imamura,Takahisa; Yoneda,Masakazu; Irie,Atsushi; Ogi,Hidenao; Nagata,Masashi; Yoshida,Ryoji; Fukuma,Daiki; Kawahara,Kenta; Shinohara,Masanori; Nakayama,Hideki

doi:10.3892/ijo.2016.3653

Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis

Authors:
- Takuya Tanaka
- Takahisa Imamura
- Masakazu Yoneda
- Atsushi Irie
- Hidenao Ogi
- Masashi Nagata
- Ryoji Yoshida
- Daiki Fukuma
- Kenta Kawahara
- Masanori Shinohara
- Hideki Nakayama
View Affiliations

Affiliations: Department of Oral and Maxillofacial Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan, Department of Molecular Pathology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan, Department of Immunogenetics, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Published online on: August 10, 2016 https://doi.org/10.3892/ijo.2016.3653
Pages: 1377-1384

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

To study the role of TNF-α in tongue cancer metastasis, we made highly metastatic cells from a human oral squamous cell carcinoma cell line (SAS) by repeating the passage in which the cells were injected into a nude mouse tongue and harvested from metastasized cervical lymph nodes. Cancer cells after 5 passages (GSAS/N5) increased invasive activity 7-fold in a TNF-α receptor 1 (TNFR1)-dependent manner and enhanced mRNA expression of TNF-α and TNFR1. In the highly metastatic cells, NF-κB activation was upregulated via elevated phosphorylation of Akt and Ikkα/β in the signaling pathway and secretion of TNF-α, active MMP-2 and MMP-9 increased. Suppression of increase of TNF-α mRNA expression and MMP secretion by NF-κB inhibitor NBD peptide suggested a positive feedback loop in GSAS/N5 cells; TNF-α activates NF-κB and activated NF-κB induces further TNF-α secretion, leading to increase of active MMP release and promotion of invasion and metastasis of the cells. GSAS/N5 cells that had been injected into the nude mouse tongue and harvested from metastasized lungs multiplied angiopoietin-like 4 (angptl4) expression with enhanced migration activity, which indicated a possible involvement of angptl4 in lung metastasis of the cells. These results suggest that TNF-α and angptl4 promote metastasis of the oral cancer cells, thus, these molecules may be therapeutic targets for patients with tongue cancer.

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	Kalnins IK, Leonard AG, Sako K, Razack MS and Shedd DP: Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Am J Surg. 134:450–454. 1977. View Article : Google Scholar : PubMed/NCBI
3	Schuller DE, McGuirt WF, McCabe BF and Young D: The prognostic significance of metastatic cervical lymph nodes. Laryngoscope. 90:557–570. 1980. View Article : Google Scholar : PubMed/NCBI
4	Snow GB, Annyas AA, van Slooten EA, Bartelink H and Hart AA: Prognostic factors of neck node metastasis. Clin Otolaryngol Allied Sci. 7:185–192. 1982. View Article : Google Scholar : PubMed/NCBI
5	Grandi C, Alloisio M, Moglia D, Podrecca S, Sala L, Salvatori P and Molinari R: Prognostic significance of lymphatic spread in head and neck carcinomas: Therapeutic implications. Head Neck Surg. 8:67–73. 1985. View Article : Google Scholar : PubMed/NCBI
6	Chi AC, Day TA and Neville BW: Oral cavity and oropharyngeal squamous cell carcinoma - an update. CA Cancer J Clin. 65:401–421. 2015. View Article : Google Scholar : PubMed/NCBI
7	Sano D and Myers JN: Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev. 26:645–662. 2007. View Article : Google Scholar : PubMed/NCBI
8	Ho CM, Lam KH, Wei WI, Lau SK and Lam LK: Occult lymph node metastasis in small oral tongue cancers. Head Neck. 14:359–363. 1992. View Article : Google Scholar : PubMed/NCBI
9	Myers EN and Simental AA Jr: Cancer of the oral cavity. Cancer of the head and neck. 4th edition. Myers EN, Suen JY, Myers JN and Hanna EY: Elsevier; pp. 279–319. 2004
10	Teichgraeber JF and Clairmont AA: The incidence of occult metastases for cancer of the oral tongue and floor of the mouth: Treatment rationale. Head Neck Surg. 7:15–21. 1984. View Article : Google Scholar : PubMed/NCBI
11	Cunningham MJ, Johnson JT, Myers EN, Schramm VL Jr and Thearle PB: Cervical lymph node metastasis after local excision of early squamous cell carcinoma of the oral cavity. Am J Surg. 152:361–366. 1986. View Article : Google Scholar : PubMed/NCBI
12	Fakih AR, Rao RS and Patel AR: Prophylactic neck dissection in squamous cell carcinoma of oral tongue: A prospective randomized study. Semin Surg Oncol. 5:327–330. 1989. View Article : Google Scholar : PubMed/NCBI
13	Lydiatt DD, Robbins KT, Byers RM and Wolf PF: Treatment of stage I and II oral tongue cancer. Head Neck. 15:308–312. 1993. View Article : Google Scholar : PubMed/NCBI
14	Yuen AP, Wei WI, Wong YM and Tang KC: Elective neck dissection versus observation in the treatment of early oral tongue carcinoma. Head Neck. 19:583–588. 1997. View Article : Google Scholar : PubMed/NCBI
15	Yuen AP, Lam KY, Chan AC, Wei WI, Lam LK, Ho WK and Ho CM: Clinicopathological analysis of elective neck dissection for N0 neck of early oral tongue carcinoma. Am J Surg. 177:90–92. 1999. View Article : Google Scholar
16	Müller S, Pan Y, Li R and Chi AC: The Emory University Experience: Changing trends in oral squamous cell carcinoma with particular reference to young patients: 1971–2006. The Emory University experience. Head Neck Pathol. 2:60–66. 2008. View Article : Google Scholar
17	Patel SC, Carpenter WR, Tyree S, Couch ME, Weissler M, Hackman T, Hayes DN, Shores C and Chera BS: Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol. 29:1488–1494. 2011. View Article : Google Scholar : PubMed/NCBI
18	Toporcov TN, Znaor A, Zhang ZF, Yu GP, Winn DM, Wei Q, Vilensky M, Vaughan T, Thomson P, Talamini R, et al: Risk factors for head and neck cancer in young adults: A pooled analysis in the INHANCE consortium. Int J Epidemiol. 44:169–185. 2015. View Article : Google Scholar : PubMed/NCBI
19	Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB and Goeddel DV: Human tumour necrosis factor: Precursor structure, expression and homology to lymphotoxin. Nature. 312:724–729. 1984. View Article : Google Scholar : PubMed/NCBI
20	Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, et al: A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature. 385:729–733. 1997. View Article : Google Scholar : PubMed/NCBI
21	Locksley RM, Killeen N and Lenardo MJ: The TNF and TNF receptor superfamilies: Integrating mammalian biology. Cell. 104:487–501. 2001. View Article : Google Scholar : PubMed/NCBI
22	Balkwill F: Tumour necrosis factor and cancer. Nat Rev Cancer. 9:361–371. 2009. View Article : Google Scholar : PubMed/NCBI
23	Fràter-Schröder M, Risau W, Hallmann R, Gautschi P and Böhlen P: Tumor necrosis factor type α, a potent inhibitor of endothelial cell growth in vitro, is angiogenic in vivo. Proc Natl Acad Sci USA. 84:5277–5281. 1987. View Article : Google Scholar
24	Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V and Nuseir N: Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature. 329:630–632. 1987. View Article : Google Scholar : PubMed/NCBI
25	Malik STA, Naylor MS, East N, Oliff A and Balkwill FR: Cells secreting tumour necrosis factor show enhanced metastasis in nude mice. Eur J Cancer. 26:1031–1034. 1990. View Article : Google Scholar : PubMed/NCBI
26	Orosz P, Echtenacher B, Falk W, Rüschoff J, Weber D and Männel DN: Enhancement of experimental metastasis by tumor necrosis factor. J Exp Med. 177:1391–1398. 1993. View Article : Google Scholar : PubMed/NCBI
27	Tanaka T, Nakayama H, Yoshitake Y, Irie A, Nagata M, Kawahara K, Takamune Y, Yoshida R, Nakagawa Y, Ogi H, et al: Selective inhibition of nuclear factor-κB by nuclear factor-κB essential modulator-binding domain peptide suppresses the metastasis of highly metastatic oral squamous cell carcinoma. Cancer Sci. 103:455–463. 2012. View Article : Google Scholar
28	May MJ, D’Acquisto F, Madge LA, Glöckner J, Pober JS and Ghosh S: Selective inhibition of NF-kappaB activation by a peptide that blocks the interaction of NEMO with the IkappaB kinase complex. Science. 289:1550–1554. 2000. View Article : Google Scholar : PubMed/NCBI
29	Jackson-Bernitsas DG, Ichikawa H, Takada Y, Myers JN, Lin XL, Darnay BG, Chaturvedi MM and Aggarwal BB: Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene. 26:1385–1397. 2007. View Article : Google Scholar
30	Rehman AO and Wang C-Y: SDF-1α promotes invasion of head and neck squamous cell carcinoma by activating NF-kappaB. J Biol Chem. 283:19888–19894. 2008. View Article : Google Scholar : PubMed/NCBI
31	Stathopoulos GT, Kollintza A, Moschos C, Psallidas I, Sherrill TP, Pitsinos EN, Vassiliou S, Karatza M, Papiris SA, Graf D, et al: Tumor necrosis factor-alpha promotes malignant pleural effusion. Cancer Res. 67:9825–9834. 2007. View Article : Google Scholar : PubMed/NCBI
32	Kagoya Y, Yoshimi A, Kataoka K, Nakagawa M, Kumano K, Arai S, Kobayashi H, Saito T, Iwakura Y and Kurokawa M: Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity. J Clin Invest. 124:528–542. 2014. View Article : Google Scholar : PubMed/NCBI
33	Epanchintsev A, Shyamsunder P, Verma RS and Lyakhovich A: IL-6, IL-8, MMP-2, MMP-9 are overexpressed in Fanconi anemia cells through a NF-κB/TNF-α dependent mechanism. Mol Carcinog. 54:1686–1699. 2015. View Article : Google Scholar
34	Shi M, Cao M, Song J, Liu Q, Li H, Meng F, Pan Z, Bai J and Zheng J: PinX1 inhibits the invasion and metastasis of human breast cancer via suppressing NF-κB/MMP-9 signaling pathway. Mol Cancer. 14:662015. View Article : Google Scholar
35	Lai WW, Hsu SC, Chueh FS, Chen YY, Yang JS, Lin JP, Lien JC, Tsai CH and Chung JG: Quercetin inhibits migration and invasion of SAS human oral cancer cells through inhibition of NF-κB and matrix metalloproteinase-2/-9 signaling pathways. Anticancer Res. 33:1941–1950. 2013.PubMed/NCBI
36	Egeblad M and Werb Z: New functions for the matrix metal-loproteinases in cancer progression. Nat Rev Cancer. 2:161–174. 2002. View Article : Google Scholar : PubMed/NCBI
37	Littlepage LE, Sternlicht MD, Rougier N, Phillips J, Gallo E, Yu Y, Williams K, Brenot A, Gordon JI and Werb Z: Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 70:2224–2234. 2010. View Article : Google Scholar : PubMed/NCBI
38	Bates RC and Mercurio AM: Tumor necrosis factor-α stimulates the epithelial-to-mesenchymal transition of human colonic organoids. Mol Biol Cell. 14:1790–1800. 2003. View Article : Google Scholar : PubMed/NCBI
39	Santulli G: Angiopoietin-like proteins: A comprehensive look. Front Endocrinol (Lausanne). 5:42014.
40	Zhu P, Tan MJ, Huang RL, Tan CK, Chong HC, Pal M, Lam CR, Boukamp P, Pan JY, Tan SH, et al: Angiopoietin-like 4 protein elevates the prosurvival intracellular O₂⁻:H₂O₂ ratio and confers anoikis resistance to tumors. Cancer Cell. 19:401–415. 2011. View Article : Google Scholar : PubMed/NCBI
41	Huang RL, Teo Z, Chong HC, Zhu P, Tan MJ, Tan CK, Lam CRI, Sng MK, Leong DTW, Tan SM, et al: ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood. 118:3990–4002. 2011. View Article : Google Scholar : PubMed/NCBI
42	Li H, Ge C, Zhao F, Yan M, Hu C, Jia D, Tian H, Zhu M, Chen T, Jiang G, et al: Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma. Hepatology. 54:910–919. 2011. View Article : Google Scholar : PubMed/NCBI
43	Shibata K, Nakayama T, Hirakawa H, Hidaka S and Nagayasu T: Clinicopathological significance of angiopoietin-like protein 4 expression in oesophageal squamous cell carcinoma. J Clin Pathol. 63:1054–1058. 2010. View Article : Google Scholar : PubMed/NCBI
44	Minn AJ, Gupta GP, Padua D, Bos P, Nguyen DX, Nuyten D, Kreike B, Zhang Y, Wang Y, Ishwaran H, et al: Lung metastasis genes couple breast tumor size and metastatic spread. Proc Natl Acad Sci USA. 104:6740–6745. 2007. View Article : Google Scholar : PubMed/NCBI
45	Wang Z, Han B, Zhang Z, Pan J and Xia H: Expression of angiopoietin-like 4 and tenascin C but not cathepsin C mRNA predicts prognosis of oral tongue squamous cell carcinoma. Biomarkers. 15:39–46. 2010. View Article : Google Scholar