Matrix metalloproteinase 12 expression is associated with tumor FOXP3+ regulatory T cell infiltration and poor prognosis in hepatocellular carcinoma

He,Min‑Ke; Le,Yong; Zhang,Yong‑Fa; Ouyang,Han‑Yue; Jian,Pei‑En; Yu,Zi‑Shan; Wang,Li‑Juan; Shi,Ming

doi:10.3892/ol.2018.8642

Matrix metalloproteinase 12 expression is associated with tumor FOXP3+ regulatory T cell infiltration and poor prognosis in hepatocellular carcinoma

Authors:
- Min‑Ke He
- Yong Le
- Yong‑Fa Zhang
- Han‑Yue Ouyang
- Pei‑En Jian
- Zi‑Shan Yu
- Li‑Juan Wang
- Ming Shi
View Affiliations

Affiliations: Department of Hepatobiliary Oncology, Cancer Center, Sun Yat‑Sen University, Guangzhou, Guangdong 510060, P.R. China
Published online on: May 4, 2018 https://doi.org/10.3892/ol.2018.8642
Pages: 475-482

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

Hepatocellular carcinoma (HCC) is among the most fatal types of cancer worldwide due to its high rates of recurrence and metastasis. The molecular processes involved in HCC progression require further investigation to identify biomarkers for use in diagnosis and treatment. In the present study, the significance and prognostic value of matrix metallopeptidase 12 (MMP12) expression in human HCC was investigated. MMP12 mRNA expression was investigated using reverse transcription‑quantitative polymerase chain reaction analysis of 42 pairs of tumor and non‑tumor liver tissues obtained from patients with HCC following surgical treatment. Immunohistochemical staining was used to detect MMP12 and forkhead box P3 (FOXP3) expression in 158 paraffin‑embedded HCC tissues. The prognostic value of MMP12 expression was determined using Kaplan‑Meier analysis and the Cox proportional hazards model. MMP12 mRNA levels were significantly higher in liver tumor tissues compared with matched non‑tumor liver tissues. MMP12 expression and FOXP3+ regulatory T cell (Treg) infiltration was positively correlated (r=0.302; P<0.001). MMP12 protein overexpression was positively correlated with tumor size (P=0.018), high serum alpha‑fetoprotein levels (P=0.005) and poor overall survival time (P=0.012) in patients with HCC. Furthermore, MMP12 protein level was an independent predictive factor for overall survival time of patients with HCC who underwent curative resection. In conclusion, these results suggest that MMP12 may increase FOXP3+ Treg infiltration into tumor tissues, and promote tumor progression and immune evasion of HCC. The overexpression of MMP12 protein is, therefore, a valuable prognostic indicator in patients with HCC.

View Figures

View References

1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
3	Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P and Patt YZ: Risk factors for hepatocellular carcinoma: Synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 36:1206–1213. 2002. View Article : Google Scholar : PubMed/NCBI
4	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
5	Villanueva A, Hoshida Y, Battiston C, Tovar V, Sia D, Alsinet C, Cornella H, Liberzon A, Kobayashi M, Kumada H, et al: Combining clinical, pathology, and gene expression data to predict recurrence of hepatocellular carcinoma. Gastroenterology. 140:1501–1512.e2. 2011. View Article : Google Scholar : PubMed/NCBI
6	Bruix J, Boix L, Sala M and Llovet JM: Focus on hepatocellular carcinoma. Cancer Cell. 5:215–219. 2004. View Article : Google Scholar : PubMed/NCBI
7	Shapiro SD, Kobayashi DK and Ley TJ: Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem. 268:23824–23829. 1993.PubMed/NCBI
8	Nagase H and Woessner JF Jr: Matrix metalloproteinases. J Biol Chem. 274:21491–21494. 1999. View Article : Google Scholar : PubMed/NCBI
9	Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melén E, Söderhäll C, Hallberg J, et al: MMP12, lung function, and COPD in high-risk populations. N Engl J Med. 361:2599–2608. 2009. View Article : Google Scholar : PubMed/NCBI
10	Kerkelä E, Ala-Aho R, Jeskanen L, Rechardt O, Grénman R, Shapiro SD, Kähäri VM and Saarialho-Kere U: Expression of human macrophage metalloelastase (MMP-12) by tumor cells in skin cancer. J Invest Dermatol. 114:1113–1119. 2000. View Article : Google Scholar : PubMed/NCBI
11	Curci JA, Liao S, Huffman MD, Shapiro SD and Thompson RW: Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J Clin Invest. 102:1900–1910. 1998. View Article : Google Scholar : PubMed/NCBI
12	Kerkelä E, Ala-aho R, Klemi P, Grénman S, Shapiro SD, Kähäri VM and Saarialho-Kere U: Metalloelastase (MMP-12) expression by tumour cells in squamous cell carcinoma of the vulva correlates with invasiveness, while that by macrophages predicts better outcome. J Pathol. 198:258–269. 2002. View Article : Google Scholar : PubMed/NCBI
13	Cheng P, Jiang FH, Zhao LM, Dai Q, Yang WY, Zhu LM, Wang BJ, Xu C, Bao YJ and Zhang YJ: Human macrophage metalloelastase correlates with angiogenesis and prognosis of gastric carcinoma. Dig Dis Sci. 55:3138–3146. 2010. View Article : Google Scholar : PubMed/NCBI
14	Yang W, Arii S, Gorrin-Rivas MJ, Mori A, Onodera H and Imamura M: Human macrophage metalloelastase gene expression in colorectal carcinoma and its clinicopathologic significance. Cancer. 91:1277–1283. 2001. View Article : Google Scholar : PubMed/NCBI
15	Cho NH, Hong KP, Hong SH, Kang S, Chung KY and Cho SH: MMP expression profiling in recurred stage IB lung cancer. Oncogene. 23:845–851. 2004. View Article : Google Scholar : PubMed/NCBI
16	Li Y, Jia JH, Kang S, Zhang XJ, Zhao J, Wang N, Zhou RM, Sun DL, Duan YN and Wang DJ: The functional polymorphisms on promoter region of matrix metalloproteinase-12, −13 genes may alter the risk of epithelial ovarian carcinoma in Chinese. Int J Gynecol Cancer. 19:129–133. 2009. View Article : Google Scholar : PubMed/NCBI
17	Balaz P, Friess H, Kondo Y, Zhu Z, Zimmermann A and Buchler MW: Human macrophage metalloelastase worsens the prognosis of pancreatic cancer. Ann Surg. 235:519–527. 2002. View Article : Google Scholar : PubMed/NCBI
18	Gershon RK and Kondo K: Cell interactions in the induction of tolerance: The role of thymic lymphocytes. Immunology. 18:723–737. 1970.PubMed/NCBI
19	Sakaguchi S, Yamaguchi T, Nomura T and Ono M: Regulatory T cells and immune tolerance. Cell. 133:775–787. 2008. View Article : Google Scholar : PubMed/NCBI
20	Yagi H, Nomura T, Nakamura K, Yamazaki S, Kitawaki T, Hori S, Maeda M, Onodera M, Uchiyama T, Fujii S and Sakaguchi S: Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells. Int Immunol. 16:1643–1656. 2004. View Article : Google Scholar : PubMed/NCBI
21	Campbell DJ and Ziegler SF: FOXP3 modifies the phenotypic and functional properties of regulatory T cells. Nat Rev Immunol. 7:305–310. 2007. View Article : Google Scholar : PubMed/NCBI
22	Fontenot JD, Gavin MA and Rudensky AY: Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 4:330–336. 2003. View Article : Google Scholar : PubMed/NCBI
23	Hori S, Nomura T and Sakaguchi S: Control of regulatory T cell development by the transcription factor Foxp3. Science. 299:1057–1061. 2003. View Article : Google Scholar : PubMed/NCBI
24	Khattri R, Cox T, Yasayko SA and Ramsdell F: Pillars article: An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4: 337–342. J Immunol. 198:993–998. 2017.PubMed/NCBI
25	Tanaka A and Sakaguchi S: Regulatory T cells in cancer immunotherapy. Cell Res. 27:109–118. 2017. View Article : Google Scholar : PubMed/NCBI
26	Schreiber TH: The use of FoxP3 as a biomarker and prognostic factor for malignant human tumors. Cancer Epidemiol Biomarkers Prev. 16:1931–1934. 2007. View Article : Google Scholar : PubMed/NCBI
27	World medical association declaration of helsinki: Ethical principles for medical research involving human subjects. JAMA. 284:3043–3045. 2000. View Article : Google Scholar : PubMed/NCBI
28	Xu J, Ding T, He Q, Yu XJ, Wu WC, Jia WH, Yun JP, Zhang Y, Shi M, Shao CK, et al: An in situ molecular signature to predict early recurrence in hepatitis B virus-related hepatocellular carcinoma. J Hepatol. 57:313–321. 2012. View Article : Google Scholar : PubMed/NCBI
29	Edge SB and Compton CC: The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
30	Edmondson HA and Steiner PE: Primary carcinoma of the liver: A study of 100 cases among 48,900 necropsies. Cancer. 7:462–503. 1954. View Article : Google Scholar : PubMed/NCBI
31	Huang W, Hennrick K and Drew S: A colorful future of quantitative pathology: Validation of Vectra technology using chromogenic multiplexed immunohistochemistry and prostate tissue microarrays. Hum Pathol. 44:29–38. 2013. View Article : Google Scholar : PubMed/NCBI
32	Li L, Xu L, Yan J, Zhen ZJ, Ji Y, Liu CQ, Lau WY, Zheng L and Xu J: CXCR2-CXCL1 axis is correlated with neutrophil infiltration and predicts a poor prognosis in hepatocellular carcinoma. J Exp Clin Cancer Res. 34:1292015. View Article : Google Scholar : PubMed/NCBI
33	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
34	Ng KT, Qi X, Kong KL, Cheung BY, Lo CM, Poon RT, Fan ST and Man K: Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with poor prognosis of hepatocellular carcinoma. Eur J Cancer. 47:2299–2305. 2011. View Article : Google Scholar : PubMed/NCBI
35	Gorrin-Rivas MJ, Arii S, Mori A, Takeda Y, Mizumoto M, Furutani M and Imamura M: Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma. Ann Surg. 231:67–73. 2000. View Article : Google Scholar : PubMed/NCBI
36	Shimizu-Hirota R, Xiong W, Baxter BT, Kunkel SL, Maillard I, Chen XW, Sabeh F, Liu R, Li XY and Weiss SJ: MT1-MMP regulates the PI3Kδ Mi-2/NuRD-dependent control of macrophage immune function. Genes Dev. 26:395–413. 2012. View Article : Google Scholar : PubMed/NCBI
37	Marchant DJ, Bellac CL, Moraes TJ, Wadsworth SJ, Dufour A, Butler GS, Bilawchuk LM, Hendry RG, Robertson AG, Cheung CT, et al: A new transcriptional role for matrix metalloproteinase-12 in antiviral immunity. Nat Med. 20:493–502. 2014. View Article : Google Scholar : PubMed/NCBI
38	Page-McCaw A, Ewald AJ and Werb Z: Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol. 8:221–233. 2007. View Article : Google Scholar : PubMed/NCBI
39	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
40	Qu P, Yan C and Du H: Matrix metalloproteinase 12 overexpression in myeloid lineage cells plays a key role in modulating myelopoiesis, immune suppression and lung tumorigenesis. Cancer Res. 117:4476–4489. 2011.