Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Correlation of TNFAIP8 overexpression with the proliferation, metastasis, and disease-free survival in endometrial cancer

Abstract

Tumor necrosis factor alpha-induced protein 8 (TNFAIP8) is an apoptosis regulator proven to have an important function in the proliferation, invasion, metastasis, and progression of malignancies. In this study, we investigated the clinical role of TNFAIP8 overexpression in endometrial cancer (EC) and determined the relationship of TNFAIP8 with the proliferative antigen Ki-67 and metastasis-related gene matrix metallopeptidase 9 (MMP9) in 225 tumor specimens by immunohistochemistry and western blot, in order to elucidate more information on the role of TNFAIP8 protein with regard to the pathogenesis of EC. An association was observed between TNFAIP8 overexpression and clinicopathologic factors, such as advanced International Federation of Gynecology and Obstetrics stage (P < 0.001), higher histologic grade (P = 0.017), deep myometrial invasion (P = 0.030), lymphovascular space invasion (P = 0.011), lymph node metastasis (P < 0.001), and recurrence. Furthermore, TNFAIP8 overexpression was strongly correlated with MMP9 and Ki-67 expression in the progression of ECs. Patients with high expression of TNFAIP8 (P < 0.001 for both) and Ki-67 (P = 0.007 and P = 0.008) had poor overall survival and disease-free survival (DFS) rates. MMP9 overexpression did not affect survival outcomes (P > 0.05). Multivariate Cox regression analysis revealed that TNFAIP8 (P = 0.029) and lymph node metastasis (P = 0.022) were independent factors of DFS in patients with EC. These findings suggested that TNFAIP8 may be used as a prognostic marker for the recurrence of EC, and its promotion of the proliferation and metastasis in EC may be due to its mediation of Ki-67 and MMP9.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Ronnett B, Zaino R, Ellenson L, Kurman R. Endometrial carcinoma. Blaustein’s pathology of the female genital tract. 5th ed. New York: Springer; 2002. p. 501–59.

  2. 2.

    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. American Cancer Society. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8–29.

  3. 3.

    Del Carmen MG, Boruta 2nd DM, Schorge JO. Recurrent endometrial cancer. Clin Obstet Gynecol. 2011;54:266–77.

  4. 4.

    Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277–300.

  5. 5.

    Ueda SM, Kapp DS, Cheung MK, Shin JY, Osann K, Husain A, et al. Trends in demographic and clinical characteristics in women diagnosed with corpus cancer and their potential impact on the increasing number of deaths. Am J Obstet Gynecol. 2008;198:218. e1-6.

  6. 6.

    Patel S, Wang FH, Whiteside TL, Kasid U. Identification of seven differentially displayed transcripts in human primary and matched metastatic head and neck squamous cell carcinoma cell lines: implications in metastasis and/or radiation response. Oral Oncol. 1997;33:197–203.

  7. 7.

    Zhang C, Kallakury BV, Ross JS, Mewani RR, Sheehan CE, Sakabe I, et al. The significance of TNFAIP8 in prostate cancer response to radiation and docetaxel and disease recurrence. Int J Cancer. 2013;133:31–42.

  8. 8.

    Liu K, Qin CK, Wang ZY, Liu SX, Cui XP, Zhang DY. Expression of tumor necrosis factor-alpha-induced protein 8 in pancreas tissues and its correlation with epithelial growth factor receptor levels. Asian Pac J Cancer Prev. 2012;13:847–50.

  9. 9.

    Hadisaputri YE, Miyazaki T, Suzuki S, Yokobori T, Kobayashi T, Tanaka N, et al. TNFAIP8 overexpression: clinical relevance to esophageal squamous cell carcinoma. Ann Surg Oncol. 2012;19 Suppl 3:S589–96.

  10. 10.

    Dong QZ, Zhao Y, Liu Y, Wang Y, Zhang PX, Jiang GY, et al. Overexpression of SCC-S2 correlates with lymph node metastasis and poor prognosis in patients with non-small-cell lung cancer. Cancer Sci. 2010;101:1562–9.

  11. 11.

    Miao Z, Zhao T, Wang Z, Xu Y, Song Y, Wu J, et al. SCC-S2 is overexpressed in colon cancers and regulates cell proliferation. Tumour Biol. 2012;33:2099–106.

  12. 12.

    Zhang C, Chakravarty D, Sakabe I, Mewani RR, Boudreau HE, Kumar D, et al. Role of SCC-S2 in experimental metastasis and modulation of VEGFR-2, MMP-1, and MMP-9 expression. Mol Ther. 2006;13:947–55.

  13. 13.

    Shi TY, Cheng X, Yu KD, Sun MH, Shao ZM, Wang MY, et al. Functional variants in TNFAIP8 associated with cervical cancer susceptibility and clinical outcomes. Carcinogenesis. 2013;34:770–8.

  14. 14.

    Liu T, Gao H, Chen X, Lou G, Gu L, Yang M, et al. TNFAIP8 as a predictor of metastasis and a novel prognostic biomarker in patients with epithelial ovarian cancer. Br J Cancer. 2013;109:1685–92.

  15. 15.

    Fridman R, Toth M, Peña D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res. 1995;55:2548–55.

  16. 16.

    Backstrom JR, Tökés ZA. The 84-kDa form of human matrix metalloproteinase-9 degrades substance P and gelatin. J Neurochem. 1995;64:1312–8.

  17. 17.

    Lin LF, Chuang CH, Li CF, Liao CC, Cheng CP, Cheng TL, et al. ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer. Cancer Res. 2010;70:192–201.

  18. 18.

    Yu F, Jiang Q, Zhou Y, Yang Z, Yu X, Wang H, et al. Abnormal expression of matrix metalloproteinase-9 (MMP9) correlates with clinical course in Chinese patients with endometrial cancer. Dis Markers. 2012;32:321–7.

  19. 19.

    McCormick D, Hall PA. The complexities of proliferating cell nuclear antigen. Histopathology. 1992;21:591–4.

  20. 20.

    Cattoretti G, Becker MH, Key G, Duchrow M, Schlüter C, Galle J, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168:357–63.

  21. 21.

    Weidner N, Moore 2nd DH, Vartanian R. Correlation of Ki-67 antigen expression with mitotic figure index and tumor grade in breast carcinomas using the novel “paraffin”-reactive MIB1 antibody. Hum Pathol. 1994;25:337–42.

  22. 22.

    Scott RJ, Hall PA, Haldane JS, van Noorden S, Price Y, Lane DP, et al. A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction. J Pathol. 1991;165:173–8.

  23. 23.

    Jacks T, Weinberg RA. Cell-cycle control and its watchman. Nature. 1996;381:643–4.

  24. 24.

    Kinzler KW, Vogelstein B. Life (and death) in a malignant tumour. Nature. 1996;379:19–20.

  25. 25.

    Gerdes J, Lemke H, Baisch H, Wacker HH, Schwab U, Stein H. Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. J Immunol. 1984;133:1710–5.

  26. 26.

    Amant F, Moerman P, Neven P, Timmerman D, Van Limbergen E, Vergote I. Endometrial cancer. Lancet. 2005;366:491–505.

  27. 27.

    Vance S, Yechieli R, Cogan C, Hanna R, Munkarah A, Elshaikh MA. The prognostic significance of age in surgically staged patients with Type II endometrial carcinoma. Gynecol Oncol. 2012;126:16–9.

  28. 28.

    Brown AK, Madom L, Moore R, Granai CO, DiSilvestro P. The prognostic significance of lower uterine segment involvement in surgically staged endometrial cancer patients with negative nodes. Gynecol Oncol. 2007;105:55–8.

  29. 29.

    Rose PG. Endometrial carcinoma. N Engl J Med. 1996;335:640–9.

  30. 30.

    Rotman M, Aziz H, Halpern J, Schwartz D, Sohn C, Choi K. Endometrial carcinoma. Influence of prognostic factors on radiation management. Cancer. 1993;71:1471–9.

  31. 31.

    Chieng DC, Rodriguez-Buford C, Grizzle WA. Role of immunohistochemical expression of Lewis Y antigen in ovarian carcinoma. In: Hayat MA, editor. Immunohistochemistry and in situ hybridization of human carcinomas, vol. 4. Burlington: Elsevier; 2006. p. 465–71.

  32. 32.

    Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M, et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol. 2005;23:8664–70.

  33. 33.

    Shibata K, Kikkawa F, Mizokami Y, Kajiyama H, Ino K, Nomura S, et al. Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma. Tumour Biol. 2005;26:9–16.

  34. 34.

    Hall PA, Woods AL. Immunohistochemical markers of cellular proliferation: achievements, problems and prospects. Cell Tissue Kinet. 1990;23:505–22.

  35. 35.

    Bowen ID, Bowen SM, Jones A. Mitosis and apoptosis. London: Chapman and Hall; 1998.

  36. 36.

    Stefansson IM, Salvesen HB, Immervoll H, Akslen LA. Prognostic impact of histological grade and vascular invasion compared with tumour cell proliferation inendometrial carcinoma of endometrioid type. Histopathology. 2004;44:472–9.

  37. 37.

    Salvesen HB, Iversen OE, Akslen LA. Prognostic significance of angiogenesis and Ki-67, p53, and p21 expression: a population-based endometrial carcinoma study. J Clin Oncol. 1999;17:1382–90.

  38. 38.

    Geisler JP, Geisler HE, Miller GA, Wiemann MC, Zhou Z, Crabtree W. MIB-1 in endometrial carcinoma: prognostic significance with 5-year follow-up. Gynecol Oncol. 1999;75:432–6.

  39. 39.

    Nordström B, Strang P, Bergström R, Nilsson S, Tribukait B. A comparison of proliferation markers and their prognostic value for women with endometrial carcinoma. Ki-67, proliferating cell nuclear antigen, and flow cytometric S-phase fraction. Cancer. 1996;78:1942–51.

  40. 40.

    Liotta LA. Tumor invasion and metastases–role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res. 1986;46:1–7.

  41. 41.

    Park DW, Ryu HS, Choi DS, Park YH, Chang KH, Min CK. Localization of matrix metalloproteinases on endometrial cancer cell invasion in vitro. Gynecol Oncol. 2001;82:442–9.

  42. 42.

    Kumar D, Gokhale P, Broustas C, Chakravarty D, Ahmad I, Kasid U. Expression of SCC-S2, an antiapoptotic molecule, correlates with enhanced proliferation and tumorigenicity of MDA-MB 435 cells. Oncogene. 2004;23(2):612–6.

  43. 43.

    Woodward MJ, de Boer J, Heidorn S, Hubank M, Kioussis D, Williams O, et al. TNFAIP8 is an essential gene for the regulation of glucocorticoid-mediated apoptosis of thymocytes. Cell Death Differ. 2010;17(2):316–23.

  44. 44.

    Zhang LJ, Liu X, Gafken PR, Kioussi C, Leid M. A chicken ovalbumin upstream promoter transcription factor I (COUP-TFI) complex represses expression of the gene encoding tumor necrosis factor alpha-induced protein 8 (TNFAIP8). J Biol Chem. 2009;284(10):6156–68.

  45. 45.

    Laliberté B, Wilson AM, Nafisi H, Mao H, Zhou YY, Daigle M, et al. TNFAIP8: a new effector for Galpha(i) coupling to reduce cell death and induce cell transformation. J Cell Physiol. 2010;225(3):865–74.

  46. 46.

    Hedrick Ellenson L, Ronnett BM, Soslow RA, Zaino RJ, Kurman RJ. Endometrial carcinoma. In: Kurman RJ, Hedrick Ellenson L, Ronnett BM, editors. Blaustein’s pathology of the female genital tract. 6th ed. New York: Springer; 2011. p. 394–456.

  47. 47.

    Silverberg SG, Kurman RJ, Nogales F, Mutter GL, Kubik-Huch RA, Tavassoli FA. Epithelial tumours and related lesion. In: Tavassoli FA, Devilee P, editors. World health organization classification of tumours pathology and genetics tumours of the breast and female genital organs. Lyon: IARC; 2003. p. 217–61.

Download references

Acknowledgments

We thank all the people and patients who had participated in this study.

Conflicts of interest

None

Author information

Correspondence to Ge Lou.

Additional information

Tianbo Liu and Hongyu Gao contributed equally to this article.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liu, T., Gao, H., Yang, M. et al. Correlation of TNFAIP8 overexpression with the proliferation, metastasis, and disease-free survival in endometrial cancer. Tumor Biol. 35, 5805–5814 (2014). https://doi.org/10.1007/s13277-014-1770-y

Download citation

Keywords

  • Tumor necrosis factor alpha-induced protein 8
  • Endometrial cancer
  • Disease-free survival
  • Proliferation
  • Metastasis