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Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma

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Abstract

The purpose of this study was to assess the value of cytokeratin 19 (CK19) and matrix metalloproteinase 2 (MMP-2) in predicting lymph node metastasis (LNM) and survival after curative resection in hepatocellular carcinoma (HCC) patients. Expression of CK19 and MMP-2 in tumor tissue was assessed through immunohistochemical staining of tissue microarrays (TMAs), which were constructed using samples from HCC patients with (n = 123) and without (n = 145) LNM. Positive CK19 expression was correlated with LNM (P < 0.001), satellite lesions (P = 0.016), and lymph node location (P = 0.039). High MMP-2 expression correlated with LNM (P < 0.001), UICC T stage (P = 0.023), and Edmondson grade (P = 0.022). Moreover, CK19 expression correlated with MMP-2 expression (P = 0.033). CK19 and MMP-2 expression were predictive of HCC LNM (AUC: 0.640; 95% CI: 0.572–0.707; P < 0.001 and AUC: 0.611; 95% CI: 0.544–0.679; P = 0.002, respectively). CK19 and MMP-2 expression were independent prognostic factors for disease-free survival (P = 0.031 and P = 0.012, respectively) and overall survival (P = 0.013 and P = 0.018, respectively) in HCC patients with LNM. CK19 expression (P < 0.001), MMP-2 expression (P = 0.006), and UICC T stage (P < 0.001) were independent risk factors for developing LNM in HCC. These findings show that CK19 and MMP-2 expression may be beneficial in predicting HCC LNM and survival.

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References

  1. Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917

    Article  PubMed  Google Scholar 

  2. Natsuizaka M, Omura T, Akaike T, Kuwata Y, Yamazaki K, Sato T, Karino Y, Toyota J, Suga T, Asaka M (2005) Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 20:1781–1787

    Article  PubMed  Google Scholar 

  3. Sun HC, Zhuang PY, Qin LX, Ye QH, Wang L, Ren N, Zhang JB, Qian YB, Lu L, Fan J, Tang ZY (2007) Incidence and prognostic values of lymph node metastasis in operable hepatocellular carcinoma and evaluation of routine complete lymphadenectomy. J Surg Oncol 96:37–45

    Article  PubMed  Google Scholar 

  4. Zeng ZC, Tang ZY, Fan J, Qin LX, Ye SL, Zhou J, Sun HC, Wang BL, Wang JH (2005) Consideration of role of radiotherapy for lymph node metastases in patients with HCC: retrospective analysis for prognostic factors from 125 patients. Int J Radiat Oncol Biol Phys 63:1067–1076

    Article  PubMed  Google Scholar 

  5. Xenidis N, Ignatiadis M, Apostolaki S, Perraki M, Kalbakis K, Agelaki S, Stathopoulos EN, Chlouverakis G, Lianidou E, Kakolyris S, Georgoulias V, Mavroudis D (2009) Cytokeratin-19 mRNA-positive circulating tumor cells after adjuvant chemotherapy in patients with early breast cancer. J Clin Oncol 27:2177–2184

    Article  PubMed  CAS  Google Scholar 

  6. Van Trappen PO, Gyselman VG, Lowe DG, Ryan A, Oram DH, Bosze P, Weekes AR, Shepherd JH, Dorudi S, Bustin SA, Jacobs IJ (2001) Molecular quantification and mapping of lymph-node micrometastases in cervical cancer. Lancet 357:15–20

    Article  PubMed  Google Scholar 

  7. Visser M, Jiwa M, Horstman A, Brink AA, Pol RP, van Diest P, Snijders PJ, Meijer CJ (2008) Intra-operative rapid diagnostic method based on CK19 mRNA expression for the detection of lymph node metastases in breast cancer. Int J Cancer 122:2562–2567

    Article  PubMed  CAS  Google Scholar 

  8. Chen TF, Jiang GL, Fu XL, Wang LJ, Qian H, Wu KL, Zhao S (2007) CK19 mRNA expression measured by reverse-transcription polymerase chain reaction (RT-PCR) in the peripheral blood of patients with non-small cell lung cancer treated by chemo-radiation: an independent prognostic factor. Lung Cancer 56:105–114

    Article  PubMed  Google Scholar 

  9. Ding SJ, Li Y, Tan YX (2004) From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics 3:73–81

    PubMed  CAS  Google Scholar 

  10. Tan H, Ye K, Wang Z, Tang H, Wang Z, Tang H (2008) Clinicopathologic evaluation of immunohistochemical CD147 and MMP-2 expression in differentiated thyroid carcinoma. Jpn J Clin Oncol 38:528–533

    Article  PubMed  Google Scholar 

  11. Patel BP, Shah SV, Shukla SN, Shah PM, Patel PS (2007) Clinical significance of MMP-2 and MMP-9 in patients with oral cancer. Head Neck 29:564–572

    Article  PubMed  Google Scholar 

  12. Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Niwa H, Tsuneyama K, Takano Y (2006) Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res 26:3579–3583

    PubMed  CAS  Google Scholar 

  13. Jinga DC, Blidaru A, Condrea I, Ardeleanu C, Dragomir C, Szegli G, Stefanescu M, Matache C (2006) MMP-9 and MMP-2 gelatinases and TIMP-1 and TIMP-2 inhibitors in breast cancer: correlations with prognostic factors. J Cell Mol Med 10:499–510

    Article  PubMed  CAS  Google Scholar 

  14. de Vicente JC, Fresno MF, Villalain L, Vega JA, Hernández Vallejo G (2005) Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma. Oral Oncol 41:283–293

    Article  PubMed  Google Scholar 

  15. Mönig SP, Baldus SE, Hennecken JK, Spiecker DB, Grass G, Schneider PM, Thiele J, Dienes HP, Hölscher AH (2001) Expression of MMP-2 is associated with progression and lymph node metastasis of gastric carcinoma. Histopathology 39:597–602

    Article  PubMed  Google Scholar 

  16. Théret N, Musso O, Turlin B, Lotrian D, Bioulac-Sage P, Campion JP, Boudjéma K, Clément B (2001) Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology 34:82–88

    Article  PubMed  Google Scholar 

  17. Li Y, Tian B, Yang J, Zhao L, Wu X, Ye SL, Liu YK, Tang ZY (2004) Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol 2004(130):460–468

    Google Scholar 

  18. Uenishi T, Kubo S, Yamamoto T, Shuto T, Ogawa M, Tanaka H, Tanaka S, Kaneda K, Hirohashi K (2003) Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci 94:851–857

    Article  PubMed  CAS  Google Scholar 

  19. Talvensaari A, Apaja-Sarkkinen M, Höyhtyä M, Westerlund A, Puistola U, Turpeenniemi T (1999) Matrix metalloproteinase 2 immunoreactive protein appears early in cervical epithelial dedifferentiation. Gynecol Oncol 72:306–311

    Article  PubMed  CAS  Google Scholar 

  20. Xiang ZL, Zeng ZC, Tang ZY, Fan J, Sun HC, Wu WZ, Tan YS (2009) Increased expression of VEGF-C and nuclear CXCR4 in hepatocellular carcinoma is correlated with lymph node metastasis and poor outcome. Cancer J 15:519–525

    Article  PubMed  Google Scholar 

  21. Zhuang PY, Zhang JB, Zhu XD, Zhang W, Wu WZ, Tan YS, Hou J, Tang ZY, Qin LX, Sun HC (2008) Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor. Cancer 112:2740–2748

    Article  PubMed  Google Scholar 

  22. Wang HY, Sun JM, Lu HF, Shi DR, Ou ZL, Ren YL, Fu SQ (2006) Micrometastases detected by cytokeratin 19 expression in sentinel lymph nodes of patients with early-stage cervical cancer. Int J Gynecol Cancer 16:643–648

    Article  PubMed  CAS  Google Scholar 

  23. Li Y, Tang ZY, Tian B, Ye SL, Qin LX, Xue Q, Sun RX (2006) Serum CYFRA 21-1 level reflects hepatocellular carcinoma metastasis: study in nude mice model and clinical patients. J Cancer Res Clin Oncol 132:515–520

    Article  PubMed  CAS  Google Scholar 

  24. Yang XR, Xu Y, Shi GM, Fan J, Zhou J, Ji Y, Sun HC, Qiu SJ, Yu B, Gao Q, He YZ, Qin WZ, Chen RX, Yang GH, Wu B, Lu Q, Wu ZQ, Tang ZY (2008) Cytokeratin 10 and cytokeratin 19: predictive markers for poor prognosis in hepatocellular carcinoma patients after curative resection. Clin Cancer Res 14:3850–3859

    Article  PubMed  CAS  Google Scholar 

  25. Mertz KD, Demichelis F, Sboner A, Hirsch MS, Dal Cin P, Struckmann K, Storz M, Scherrer S, Schmid DM, Strebel RT, Probst-Hensch NM, Gerstein M, Moch H, Rubin MA (2008) Association of cytokeratin 7 and 19 expression with genomic stability and favorable prognosis in clear cell renal cell cancer. Int J Cancer 123:569–576

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Zhao-Chong Zeng.

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Xiang, ZL., Zeng, ZC., Tang, ZY. et al. Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma. Mol Biol Rep 38, 3531–3539 (2011). https://doi.org/10.1007/s11033-010-0463-x

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  • DOI: https://doi.org/10.1007/s11033-010-0463-x

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