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Open Access 01-12-2018 | Research article

Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma

Authors: Frank K. Leusink, Eleftherios Koudounarakis, Michael H. Frank, Ronald Koole, Paul J. van Diest, Stefan M. Willems

Published in: BMC Cancer | Issue 1/2018

Abstract

Background

Lymph node metastasis (LNM) is a major determinant of prognosis and treatment planning of oral squamous cell carcinoma (OSCC). Cysteine cathepsins constitute a family of proteolytic enzymes with known role in the degradation of the extracellular matrix. Involvement in pathological processes, such as inflammation and cancer progression, has been proved. The aim of the study was to discover the clinicopathological and prognostic implications of cathepsin K (CTSK) expression in oral squamous cell carcinoma.

Methods

Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papilloma virus (HPV) status was previously determined by an algorithm for HPV-16. CTSK Protein expression was semi-quantitatively determined by immunohistochemistry in tumor and stromal cells. Expression data were correlated with various clinicopathological variables.

Results

Elevated gene and protein expression of CTSK were strongly associated to LNM and perineural invasion (p < 0.01). Logistic regression analysis highlighted increased CTSK protein expression in tumor cells as the most significant independent factor of lymphatic metastasis (OR = 7.65, CI:2.31–23.31, p = 0.001). Survival analysis demonstrated CTSK protein expression in both stromal and tumor cells as significant indicators of poor 5-year disease specific survival (HR = 2.40, CI:1.05–5.50, p = 0.038 for stromal cells; HR = 2.79, CI:1.02–7.64, p = 0.045 for tumor cells).

Conclusion

Upregulation of CTSK seems to be associated with high incidence of lymphatic spread and poor survival in OSCC. CTSK could therefore serve as a predictive biomarker for OSCC.

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90.CrossRefPubMed

Sanderson RJ, Ironside JAD. Squamous cell carcinomas of the head and neck. BMJ. 2002;325(7368):822–7.CrossRefPubMedPubMedCentral

Leusink FK, van Es RJ, de Bree R, Baatenburg de Jong RJ, van Hooff SR, Holstege FC, et al. Novel diagnostic modalities for assessment of the clinically node-negative neck in oral squamous-cell carcinoma. Lancet Oncol. 2012;13(12):e554–61.CrossRefPubMed

Roepman P, Wessels LF, Kettelarij N, Kemmeren P, Miles AJ, Lijnzaad P, et al. An expression profile for diagnosis of lymph node metastases from primary head and neck squamous cell carcinomas. Nat Genet. 2005;37(2):182–6.CrossRefPubMed

Roepman P, Kemmeren P, Wessels LF, Slootweg PJ, Holstege FC. Multiple robust signatures for detecting lymph node metastasis in head and neck cancer. Cancer Res. 2006;66:2361–6.CrossRefPubMed

van Hooff SR, Leusink FK, Roepman P, Baatenburg de Jong RJ, Speel EJ, van den Brekel MW, et al. Validation of a gene expression signature for assessment of lymph node metastasis in oral squamous cell carcinoma. J Clin Oncol. 2012;30(33):4104–10.CrossRefPubMed

Turk V, Turk B, Turk D. Lysosomal cysteine proteases: facts and opportunities. EMBO J. 2001;20(17):4629–33.CrossRefPubMedPubMedCentral

Wen X, Yi LZ, Liu F, Wei JH, Xue Y. The role of cathepsin K in oral and maxillofacial disorders. Oral Dis. 2016;22:109–15.CrossRefPubMed

Siponen M, Bitu CC, Al-Samadi A, Nieminen P, Salo T. Cathepsin K expression is increased in oral lichen planus. J Oral Pathol Med. 2016;45:758–65.CrossRefPubMed

10.

Turk V, Stoka V, Vasiljeva O, Renko M, Sun T, Turk B, et al. Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim Biophys Acta. 2012;1824(1):68–88.CrossRefPubMed

11.

Kawasaki G, Kato Y, Mizuno A. Cathepsin expression in oral squamous cell carcinoma: relationship with clinicopathological factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93:446–54.CrossRefPubMed

12.

Vigneswaran N, Zhao W, Dassanayake A, Muller S, Miller DM, Zacharias W. Variable expression of cathepsin B and D correlates with highly invasive and metastatic phenotype of oral cancer. Human Pathol. 2000;31:931–7.CrossRef

13.

Wickramasinghe NS, Nagaraj NS, Vigneswaran N, Zacharias W. Cathepsin B promotes both motility and invasiveness oral carcinoma cells. Arch Biochem Biophys. 2005;436:187–95.CrossRefPubMed

14.

Yang W-E, Ho C-C, Yang S-F, Lin S-H, Yeh K-T, Lin C-W, et al. Cathepsin B expression and the correlation with clinical aspects of oral squamous cell carcinoma. PLoS One. 2016;11(3):e0152165.CrossRefPubMedPubMedCentral

15.

Bitu CC, Kauppila JH, Bufalino A, Nurmenniemi S, Teppo S, Keinänen M, et al. Cathepsin K is present in invasive oral tongue squamous cell carcinoma in vivo and in vitro. PLoS One. 2013;8(8):e70925.CrossRefPubMedPubMedCentral

16.

Yamashita K, Iwatake M, Okamoto K, Yamada S-i, Umeda M, Tsukuba T. Cathepsin K modulates invasion, migration and adhesion of oral squamous cell carcinomas in vitro. Oral Dis. 2017;23:518–25.CrossRefPubMed

17.

Leusink FK, van Diest PJ, Frank MH, Broekhuizen R, Braunius W, van Hooff SR, et al. The Co-Expression of Kallikrein 5 and Kallikrein 7 Associates with Poor Survival in Non-HPV Oral Squamous-Cell Carcinoma. Pathobiology. 2015;82(2):58–67.CrossRefPubMed

18.

Psyrri A, Gouveris P, Vermorken JB. Human papillomavirus-related head and neck tumors: clinical and research implication. Curr Opin Oncol. 2009;21:201–5.CrossRefPubMed

19.

Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell. 2011;147(2):275–92.CrossRefPubMedPubMedCentral

20.

Guo M, Mathieu PA, Linebaugh B, Sloane BF, Reiners JJ Jr. Phorbol ester activation of a proteolytic cascade capable of activating latent transforming growth factor-betaL a process initiated by the exocytosis of cathepsin B. J Biol Chem. 2002;277(17):14829–37.CrossRefPubMed

21.

Vasiljeva O, Turk B. Dual contrasting roles of cysteine cathepsins in cancer progression: apoptosis versus tumor invasion. Biochimie. 2008;90(2):380–6.CrossRefPubMed

22.

Sun T, Jiang D, Zhang L, Su Q, Mao W, Jiang C. Expression profile of cathepsins indicates the potential of cathepsins B and D as prognostic factors in breast cancer patients. Oncol Lett. 2016;11(1):575–83.CrossRefPubMed

23.

Kozlowski L, Wojtukiewicz MZ, Ostrowska H. Cathepsin a activity in primary and metastatic human melanocytic tumors. Arch Dermatol Res. 2000;292(2–3):68–71.CrossRefPubMed

24.

Chen Q, Fei J, Wu L, Jiang Z, Wu Y, Zheng Y, et al. Detection of cathepsin B, cathepsin L, cystatin C, urokinase plasminogen activator and urokinase plasminogen activator receptor in the sera of lung cancer patients. Oncol Lett. 2011;2(4):693–9.CrossRefPubMedPubMedCentral

25.

Brubaker KD, Vessella RL, True LD, Thomas R, Corey E. Cathepsin K mRNA and protein expression in prostate cancer progression. J Bone Miner Res. 2003;18(2):222–30.CrossRefPubMed

26.

Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, et al. The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 1997;57(23):5386–90.PubMed

27.

Cordes C, Bartling B, Simm A, Afar D, Lautenschläger C, Hansen G, et al. Simultaneous expression of Cathepsins B and K in pulmonary adenocarcinomas and squamous cell carcinomas predicts poor recurrence-free and overall survival. Lung Cancer. 2009;64(1):79–85.CrossRefPubMed

28.

Rapa I, Volante M, Cappia S, Rosas R, Scagliotti GV, Papotti M. Cathepsin K is selectively expressed in the stroma of lung adenocarcinoma but not in bronchioloalveolar carcinoma. A useful marker of invasive growth. Am J Clin Pathol. 2006;125(6):847–54.CrossRefPubMed

29.

Jayakumar A, Kang Y, Frederick MJ, Pak SC, Henderson Y, Holton PR, Mitsudo K, Silverman GA, EL-Naggar AK, Bromme D, Clayman GL. Inhibition of the cysteine proteinases cathepsins K and L by the serpin headpin (SERPINB13): a kinetic analysis. Arch Biochem Biophys. 2003;409:367–74.CrossRefPubMed

30.

de Koning PJ, Bovenschen N, Leusink FK, Broekhuizen R, Quadir R, van Gemert JT, et al. Downregulation of SERPINB13 expression in head and neck squamous cell carcinomas associates with poor clinical outcome. Int J Cancer. 2009;125(7):1542–50.CrossRefPubMed

31.

Schwanhäusser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, et al. Global quantification of mammalian gene expression control. Nature. 2011;473(7347):337–42.CrossRefPubMed

32.

Marchesi F, Piemonti L, Mantovani A, Allavena P. Molecular mechanisms of perineural invasion, a forgotten pathway of dissemination and metastasis. Cytokine Growth Factor Rev. 2010;21(1):77–82.CrossRefPubMed

33.

Miyake H, Hara I, Eto H. Serum level of cathepsin B and its density in men with prostate cancer as novel markers of disease progression. Anticancer Res. 2004;24(4):2573–7.PubMed

Title: Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma
Authors: Frank K. Leusink
Eleftherios Koudounarakis
Michael H. Frank
Ronald Koole
Paul J. van Diest
Stefan M. Willems
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-018-4315-8

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