Clinical Significance of Soluble Major Histocompatibility Complex Class I Chain-related A in Renal Cell Carcinoma Patients

  • Qiu, Yu (Department of Urinary Surgery, The 2nd Affiliated Hospital of Harbin Medical University) ;
  • Zhao, Ya-Kun (Department of Urinary Surgery, The 2nd Affiliated Hospital of Harbin Medical University) ;
  • Yuan, Gang-Jun (Department of Urinary Surgery, The 2nd Affiliated Hospital of Harbin Medical University) ;
  • Zhu, Qing-Guo (Department of Urinary Surgery, The 2nd Affiliated Hospital of Harbin Medical University)
  • Published : 2013.10.30


Objective: Major histocompatibility complex class I chain-related A (MICA) is a stress-inducible glycoprotein that can be shed as a soluble protein. This study was conducted to determine the expression of MICA in renal cell carcinoma (RCC) and examine the clinical relevance of soluble MICA (sMICA) in this disease. Methods: Immunohistochemistry and real-time PCR analyses were performed to assess the expression of MICA in 48 pairs of RCC and adjacent normal renal tissues. Serum levels of sMICA were measured in 48 RCC patients, 12 patients with benign renal tumors, and 20 healthy individuals. The correlations between sMICA levels and clinicopathological parameters were analyzed and the diagnostic performance of sMICA in RCC was evaluated. Results: RCCs exhibited elevated expression of MICA compared to adjacent normal tissues. Serum concentrations of sMICA were significantly greater in RCC patients ($348.5{\pm}32.5pg/ml$) than those with benign disease ($289.3{\pm}30.4pg/ml$) and healthy controls ($168.4{\pm}43.2pg/ml$) and significantly correlated with advanced tumor stage, lymph node metastasis, distant metastasis, vascular invasion, and higher histological grade. Using a cut-off point of 250 pg/ml, sMICA demonstrated a specificity and sensitivity of 63.2% and 75.6%, respectively, in distinguishing between RCC and benign renal tumors. Conclusion: MICA expression is upregulated in RCC and increased serum sMICA levels predict aggressive tumor behavior. However, the applicability of sMICA alone is limited in distinguishing RCC from benign renal tumors.


  1. Groh V, Rhinehart R, Secrist H, et al (1999). Broad tumor-associated expression and recognition by tumor-derived gamma delta T cells of MICA and MICB. Proc Natl Acad Sci U S A, 96, 6879-84.
  2. Banumathy G, Cairns P (2010). Signaling pathways in renal cell carcinoma. Cancer Biol Ther, 10, 658-64.
  3. Bauer S, Groh V, Wu J, et al (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science, 285, 727-9.
  4. Duan X, Deng L, Chen X, et al (2011). Clinical significance of the immunostimulatory MHC class I chain-related molecule A and NKG2D receptor on NK cells in pancreatic cancer. Med Oncol, 28, 466-74.
  5. Gasser S, Orsulic S, Brown EJ, Raulet DH (2005). The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature, 436, 1186-90.
  6. Groh V, Bahram S, Bauer S, et al (1996). Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci U S A, 93, 12445-50.
  7. Groh V, Wu J, Yee C, Spies T (2002). Tumour-derived soluble MIC ligands impair expression of NKG2D and T-cell activation. Nature, 419, 734-8.
  8. Holdenrieder S, Stieber P, Peterfi A, et al (2006). Soluble MICA in malignant diseases. Int J Cancer, 118, 684-7.
  9. Jensen H, Andresen L, Nielsen J, Christensen JP, Skov S (2011). Vesicular stomatitis virus infection promotes immune evasion by preventing NKG2D-ligand surface expression. PLoS One, 6, e23023.
  10. Kohga K, Takehara T, Tatsumi T, et al (2009). Anticancer chemotherapy inhibits MHC class I-related chain a ectodomain shedding by downregulating ADAM10 expression in hepatocellular carcinoma. Cancer Res, 69, 8050-7.
  11. Kohga K, Takehara T, Tatsumi T, et al (2010). Sorafenib inhibits the shedding of major histocompatibility complex class I-related chain A on hepatocellular carcinoma cells by down-regulating a disintegrin and metalloproteinase 9. Hepatology, 51, 1264-73.
  12. Livak KJ, Schmittgen TD (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-Delta Delta C(T)). Method Methods, 25, 402-8.
  13. Kohga K, Tatsumi T, Tsunematsu H, et al (2012). Interleukin-$1{\beta}$ enhances the production of soluble MICA in human hepatocellular carcinoma. Cancer Immunol Immunother, 61, 1425-32.
  14. Lam JS, Leppert JT, Belldegrun AS, Figlin RA (2005). Novel approaches in the therapy of metastatic renal cell carcinoma. World J Urol, 23, 202-12.
  15. Li JJ, Pan K, Gu MF, et al (2013). Prognostic value of soluble MICA levels in the serum of patients with advanced hepatocellular carcinoma. Chin J Cancer, 32, 141-8.
  16. Madjd Z, Spendlove I, Moss R, et al (2007). Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun, 7, 17.
  17. Motzer RJ, Russo P (2000). Systemic therapy for renal cell carcinoma. J Urol, 163, 408-17.
  18. Mustafa A, Gupta S, Hudes GR, et al (2011). Serum amino acid levels as a biomarker for renal cell carcinoma. J Urol, 186, 1206-12.
  19. Oppenheim DE, Roberts SJ, Clarke SL, et al (2005). Sustained localized expression of ligand for the activating NKG2D receptor impairs natural cytotoxicity in vivo and reduces tumor immunosurveillance. Nat Immunol, 6, 928-37.
  20. Parkin DM, Bray F, Ferlay J, Pisani P (2005). Global cancer statistics, 2002. CA Cancer J Clin, 55, 74-108.
  21. Raffaghello L, Prigione I, Airoldi I, et al (2004). Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia, 6, 558-68.
  22. Wang J, Li C, Yang D, Jian XC, Jiang CH (2012). Clinico-pathological significance of MHC-I type chain-associated protein A expression in oral squamous cell carcinoma. Asian Pac J Cancer Prev, 13, 715-8.
  23. Redova M, Poprach A, Nekvindova J, et al (2012). Circulating miR-378 and miR-451 in serum are potential biomarkers for renal cell carcinoma. J Transl Med, 10, 55.
  24. Salih HR, Holdenrieder S, Steinle A (2008). Soluble NKG2D ligands: prevalence, release, and functional impact. Front Biosci, 13, 3448-56.
  25. Tamaki S, Sanefuzi N, Kawakami M, et al (2008). Association between soluble MICA levels and disease stage IV oral squamous cell carcinoma in Japanese patients. Hum Immunol, 69, 88-93.
  26. Watson NF, Spendlove I, Madjd Z, et al (2006). Expression of the stress-related MHC class I chain-related protein MICA is an indicator of good prognosis in colorectal cancer patients. Int J Cancer, 118, 1445-52.
  27. Weber KJ, Rao G, Quiros R, et al (2004). Increased expression of MICA in serum of pancreatic cancer patients. J Am Coll Surg, 199, 89.
  28. Yamanegi K, Yamane J, Kobayashi K, et al (2012). Downregulation of matrix metalloproteinase-9 mRNA by valproic acid plays a role in inhibiting the shedding of MHC class I-related molecules A and B on the surface of human osteosarcoma cells. Oncol Rep, 28, 1585-90.
  29. Zhao S, Wang H, Nie Y, et al (2012). Midkine upregulates MICA/B expression in human gastric cancer cells and decreases natural killer cell cytotoxicity. Cancer Immunol Immunother, 61, 1745-53.