Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early‑stage pancreatic ductal adenocarcinoma

Yang,Chengkun; Yu,Tingdong; Liu,Zhengqian; Ye,Xinping; Liao,Xiwen; Wang,Xiangkun; Han,Chuangye; Zhu,Guangzhi; Qin,Wei; Peng,Tao

doi:10.3892/or.2019.7135

Cystatin F as a key family 2 cystatin subunit and prognostic biomarker for early‑stage pancreatic ductal adenocarcinoma

Authors:
- Chengkun Yang
- Tingdong Yu
- Zhengqian Liu
- Xinping Ye
- Xiwen Liao
- Xiangkun Wang
- Chuangye Han
- Guangzhi Zhu
- Wei Qin
- Tao Peng
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Affiliations: Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: April 24, 2019 https://doi.org/10.3892/or.2019.7135
Pages: 79-90
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and early diagnosis and assessment may enhance the quality of life and survival of patients. The prognostic value of key family 2 cystatins subunit in PDAC patients remains unknown. The potential molecular roles of family 2 cystatins and related pathways were investigated using bioinformatics analysis. The relationship of family 2 cystatin expression levels and clinical outcomes of 112 patients with early‑stage PDAC were evaluated via univariate and combined survival analysis. A prognostic nomogram model was also constructed and gene set enrichment analysis was performed to investigate potential pathways in PDAC. The pathways, interaction networks, and Gene Ontology term analysis of the cystatin gene family were analyzed in the present study. Cystatin F (CST7) was identified as the key subunit of family 2 cystatins in survival analysis. PDAC patients who harbored a higher expression level of CST7 had a lower risk in overall survival (adjusted HROS=0.44, 95% CI=0.25‑0.77, P=0.004) and a longer survival time in various subgroups. The prognostic nomogram indicated that the CST7 expression model effectively predicted the outcomes of patients with early‑stage PDAC (predictive ability >0.75). In the gene set enrichment analysis, it was revealed that CST7 expression may be involved in immune regulation and be associated with cell adhesion. CST7 could be a useful biomarker for the prognostic prediction of early‑stage PDAC after pancreaticoduodenectomy.

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1	Li D, Xie K, Wolff R and Abbruzzese JL: Pancreatic cancer. Lancet. 363:1049–1057. 2004. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
3	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
4	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI
5	Conrad C and Lillemoe KD: Surgical palliation of pancreatic cancer. Cancer J. 18:577–583. 2012. View Article : Google Scholar : PubMed/NCBI
6	Vincent A, Herman J, Schulick R, Hruban RH and Goggins M: Pancreatic cancer. Lancet. 378:607–620. 2011. View Article : Google Scholar : PubMed/NCBI
7	Choi EH, Kim JT, Kim JH, Kim SY, Song EY, Kim JW, Kim SY, Yeom YI, Kim IH and Lee HG: Upregulation of the cysteine protease inhibitor, cystatin SN, contributes to cell proliferation and cathepsin inhibition in gastric cancer. Clin Chim Acta. 406:45–51. 2009. View Article : Google Scholar : PubMed/NCBI
8	Travis J and Potempa J: Bacterial proteinases as targets for the development of second-generation antibiotics. Biochim Biophys Acta. 1477:35–50. 2000. View Article : Google Scholar : PubMed/NCBI
9	Koblinski JE, Ahram M and Sloane BF: Unraveling the role of proteases in cancer. Clin Chim Acta. 291:113–135. 2000. View Article : Google Scholar : PubMed/NCBI
10	Kos J and Lah TT: Cysteine proteinases and their endogenous inhibitors: Target proteins for prognosis, diagnosis and therapy in cancer (review). Oncol Rep. 5:1349–1410. 1998.PubMed/NCBI
11	Verbovšek U, Van Noorden CJ and Lah TT: Complexity of cancer protease biology: Cathepsin K expression and function in cancer progression. Semin Cancer Biol. 35:71–84. 2015. View Article : Google Scholar : PubMed/NCBI
12	Cox J: Cystatins as regulators of cancer. Med Res Arch. 5:2017. View Article : Google Scholar
13	Barrett AJ: The cystatins: A new class of peptidase inhibitors. Trends Biochem Sci. 12:193–196. 1987. View Article : Google Scholar
14	Henskens YM, Veerman EC and Nieuw Amerongen AV: Cystatins in health and disease. Biol Chem Hoppe Seyler. 377:71–86. 1996.PubMed/NCBI
15	Abrahamson M, Alvarez-Fernandez M and Nathanson CM: Cystatins. Biochem Soc Symp. 179–199. 2003. View Article : Google Scholar : PubMed/NCBI
16	Chimonidou M, Tzitzira A, Strati A, Sotiropoulou G, Sfikas C, Malamos N, Georgoulias V and Lianidou E: CST6 promoter methylation in circulating cell-free DNA of breast cancer patients. Clin Biochem. 46:235–240. 2013. View Article : Google Scholar : PubMed/NCBI
17	Cao X, Li Y, Luo RZ, Zhang L, Zhang SL, Zeng J, Han YJ and Wen ZS: Expression of Cystatin SN significantly correlates with recurrence, metastasis, and survival duration in surgically resected non-small cell lung cancer patients. Sci Rep. 5:82302015. View Article : Google Scholar : PubMed/NCBI
18	Alvarez-Díaz S, Valle N, García JM, Peña C, Freije JM, Quesada V, Astudillo A, Bonilla F, López-Otín C and Muñoz A: Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells. J Clin Invest. 119:2343–2358. 2009. View Article : Google Scholar : PubMed/NCBI
19	Hünten S and Hermeking H: p53 directly activates cystatin D/CST5 to mediate mesenchymal-epithelial transition: A possible link to tumor suppression by vitamin D3. Oncotarget. 6:15842–15856. 2015. View Article : Google Scholar : PubMed/NCBI
20	Liao X, Huang K, Huang R, Liu X, Han C, Yu L, Yu T, Yang C, Wang X and Peng T: Genome-scale analysis to identify prognostic markers in patients with early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy. Onco Targets Ther. 10:4493–4506. 2017. View Article : Google Scholar : PubMed/NCBI
21	Harrell FE Jr: rms: Regression modeling strategies. R package version 4.0-0. City. 2013.
22	Harrell FE Jr, Califf RM, Pryor DB, Lee KL and Rosati RA: Evaluating the yield of medical tests. JAMA. 247:2543–2546. 1982. View Article : Google Scholar : PubMed/NCBI
23	Koopmann J, Rosenzweig CN, Zhang Z, Canto MI, Brown DA, Hunter M, Yeo C, Chan DW, Breit SN and Goggins M: Serum markers in patients with resectable pancreatic adenocarcinoma: Macrophage inhibitory cytokine 1 versus CA19-9. Clin Cancer Res. 12:442–446. 2006. View Article : Google Scholar : PubMed/NCBI
24	Locker GY, Hamilton S, Harris J, Jessup JM, Kemeny N, Macdonald JS, Somerfield MR, Hayes DF and Bast RC Jr; ASCO: ASCO 2006 update of recommendations for the use of tumor markers in gastrointestinal cancer. J Clin Oncol. 24:5313–5327. 2006. View Article : Google Scholar : PubMed/NCBI
25	Maher K, Konjar S, Watts C, Turk B and Kopitar-Jerala N: Cystatin F regulates proteinase activity in IL-2-activated natural killer cells. Protein Pept Lett. 21:957–965. 2014. View Article : Google Scholar : PubMed/NCBI
26	Dautović E, Perišić Nanut M, Softić A and Kos J: The transcription factor C/EBPα controls the role of cystatin F during the differentiation of monocytes to macrophages. Eur J Cell Biol. 97:463–473. 2018. View Article : Google Scholar : PubMed/NCBI
27	Voigt EA, Grill DE, Zimmermann MT, Simon WL, Ovsyannikova IG, Kennedy RB and Poland GA: Transcriptomic signatures of cellular and humoral immune responses in older adults after seasonal influenza vaccination identified by data-driven clustering. Sci Rep. 8:7392018. View Article : Google Scholar : PubMed/NCBI
28	Halfon S, Ford J, Foster J, Dowling L, Lucian L, Sterling M, Xu Y, Weiss M, Ikeda M, Liggett D, et al: Leukocystatin, a new class II cystatin expressed selectively by hematopoietic cells. J Biol Chem. 273:16400–16408. 1998. View Article : Google Scholar : PubMed/NCBI
29	Ni J, Fernandez MA, Danielsson L, Chillakuru RA, Zhang J, Grubb A, Su J, Gentz R and Abrahamson M: Cystatin F is a glycosylated human low molecular weight cysteine proteinase inhibitor. J Biol Chem. 273:24797–24804. 1998. View Article : Google Scholar : PubMed/NCBI
30	Turk B, Turk D and Salvesen GS: Regulating cysteine protease activity: Essential role of protease inhibitors as guardians and regulators. Curr Pharm Des. 8:1623–1637. 2002. View Article : Google Scholar : PubMed/NCBI
31	Schüttelkopf AW, Hamilton G, Watts C and van Aalten DM: Structural basis of reduction-dependent activation of human cystatin F. J Biol Chem. 281:16570–16575. 2006. View Article : Google Scholar : PubMed/NCBI
32	Hamilton G, Colbert JD, Schuettelkopf AW and Watts C: Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis. EMBO J. 27:499–508. 2008. View Article : Google Scholar : PubMed/NCBI
33	Pham CT and Ley TJ: Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci USA. 96:8627–8632. 1999. View Article : Google Scholar : PubMed/NCBI
34	Wolters PJ, Pham CT, Muilenburg DJ, Ley TJ and Caughey GH: Dipeptidyl peptidase I is essential for activation of mast cell chymases, but not tryptases, in mice. J Biol Chem. 276:18551–18556. 2001. View Article : Google Scholar : PubMed/NCBI
35	Adkison AM, Raptis SZ, Kelley DG and Pham CT: Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis. J Clin Invest. 109:363–371. 2002. View Article : Google Scholar : PubMed/NCBI
36	Magister Š, Tseng HC, Bui VT, Kos J and Jewett A: Regulation of split anergy in natural killer cells by inhibition of cathepsins C and H and cystatin F. Oncotarget. 6:22310–22327. 2015. View Article : Google Scholar : PubMed/NCBI
37	Pierre P and Mellman I: Developmental regulation of invariant chain proteolysis controls MHC class II trafficking in mouse dendritic cells. Cell. 93:1135–1145. 1998. View Article : Google Scholar : PubMed/NCBI
38	Nathanson CM, Wassélius J, Wallin H and Abrahamson M: Regulated expression and intracellular localization of cystatin F in human U937 cells. FEBS J Biochem. 269:5502–5511. 2002. View Article : Google Scholar
39	Georgieva M, Krasteva M, Angelova E, Ralchev K, Dimitrov V, Bozhimirov S, Georgieva E and Berger MR: Analysis of the K-ras/B-raf/Erk signal cascade, p53 and CMAP as markers for tumor progression in colorectal cancer patients. Oncol Rep. 20:3–11. 2008.PubMed/NCBI
40	Utsunomiya T, Hara Y, Kataoka A, Morita M, Arakawa H, Mori M and Nishimura S: Cystatin-like metastasis-associated protein mRNA expression in human colorectal cancer is associated with both liver metastasis and patient survival. Clin Cancer Res. 8:2591–2594. 2002.PubMed/NCBI