title: Frequent expression loss of Inter-alpha-trypsin inhibitor heavy chain (ITIH) genes in multiple human solid tumors: a systematic expression analysis.
abstract: BACKGROUND
  The inter-alpha-trypsin inhibitors (ITI) are a family of plasma protease inhibitors, assembled from a light chain - bikunin, encoded by AMBP - and five homologous heavy chains (encoded by ITIH1, ITIH2, ITIH3, ITIH4, and ITIH5), contributing to extracellular matrix stability by covalent linkage to hyaluronan. So far, ITIH molecules have been shown to play a particularly important role in inflammation and carcinogenesis.
  
  
  METHODS
  We systematically investigated differential gene expression of the ITIH gene family, as well as AMBP and the interacting partner TNFAIP6 in 13 different human tumor entities (of breast, endometrium, ovary, cervix, stomach, small intestine, colon, rectum, lung, thyroid, prostate, kidney, and pancreas) using cDNA dot blot analysis (Cancer Profiling Array, CPA), semiquantitative RT-PCR and immunohistochemistry.
  
  
  RESULTS
  We found that ITIH genes are clearly downregulated in multiple human solid tumors, including breast, colon and lung cancer. Thus, ITIH genes may represent a family of putative tumor suppressor genes that should be analyzed in greater detail in the future. For an initial detailed analysis we chose ITIH2 expression in human breast cancer. Loss of ITIH2 expression in 70% of cases (n = 50, CPA) could be confirmed by real-time PCR in an additional set of breast cancers (n = 36). Next we studied ITIH2 expression on the protein level by analyzing a comprehensive tissue micro array including 185 invasive breast cancer specimens. We found a strong correlation (p < 0.001) between ITIH2 expression and estrogen receptor (ER) expression indicating that ER may be involved in the regulation of this ECM molecule.
  
  
  CONCLUSIONS
  Altogether, this is the first systematic analysis on the differential expression of ITIH genes in human cancer, showing frequent downregulation that may be associated with initiation and/or progression of these malignancies.
authors.affiliation: Institute of Pathology, University Hospital of RWTH Aachen, Aachen, Germany. alexander.hamm@rwth-aachen.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Hamm
authors.forename: Juergen
authors.initials: J
authors.lastname: Veeck
authors.forename: Nuran
authors.initials: N
authors.lastname: Bektas
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Uwe
authors.initials: U
authors.lastname: Heindrichs
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Tamra
authors.initials: T
authors.lastname: Werbowetski-Ogilvie
authors.forename: Rolando
authors.initials: R
authors.lastname: Del Maestro
authors.forename: Ruth
authors.initials: R
authors.lastname: Knuechel
authors.forename: Edgar
authors.initials: E
authors.lastname: Dahl
mesh_terms: D000510:Alpha-Globulins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics* / Q000556:secondary*; D002278:Carcinoma in Situ / Q000235:genetics*; D044584:Carcinoma, Ductal / Q000235:genetics / Q000556:secondary; D003110:Colonic Neoplasms / Q000235:genetics / Q000556:secondary; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary; D009361:Neoplasm Invasiveness / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000510:Alpha-Globulins; D012333:RNA, Messenger; C011877:inter-alpha-inhibitor