Characterization of a novel epigenetically-silenced, growth-suppressive gene, ADAMTS9, and its association with lymph node metastases in nasopharyngeal carcinoma

Hong Lok Lung, Paulisally Hau Yi Lo, Dan Xie, Suneel S. Apte, Arthur Kwok Leung Cheung, Yue Cheng, Evan Wai Lok Law, Daniel Chua, Yi Xin Zeng, Sai Wah Tsao, Eric J. Stanbridge, Maria Li Lung*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

54 Citations (Scopus)

Abstract

By using a functional complementation approach, suppression of tumorigenicity was observed after transfer of intact or truncated copies of chromosome 3 into a nasopharyngeal carcinoma (NPC) HONE1 cell line. The extra exogenous chromosome 3 in the microcell hybrids (MCHs) significantly extended the lag period of tumor formation, which may be associated with loss or inactivation of wild type alleles from the normal donor chromosome 3. Representative tumors, which grew in nude mice were reconstituted into culture and expanded as tumor segregants (TSs). In our study, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9 (ADAMTS9), a gene mapping to 3p14.2, was identified to be critically associated with tumor suppression in NPC. Gene expression analysis showed that ADAMTS9 was either not expressed or was downregulated in HONE1 cells, TSs and NPC cell lines. The mechanism of ADAMTS9 gene inactivation in the NPC cell lines and tissues was attributed to promoter hypermethylation. Using a tissue microarray and immunohistochemical staining, 31 of 66 (47%) of the NPC cases showed downregulated or absence of ADAMTS9 expression. ADAMTS9 expression was downregulated or lost in 17 of 23 (73.9%) lymph node metastatic NPC specimens, which was significantly higher than in 14 of 43 (32.6%) primary tumors. After transfection of the ADAMTS9 gene into 7 NPC cell lines, a dramatic reduction of colony forming ability was observed. These findings support ADAMTS9 as a putative tumor suppressor gene in vivo in NPC that is significantly associated with lymph node metastases.

Original languageEnglish
Pages (from-to)401-408
Number of pages8
JournalInternational Journal of Cancer
Volume123
Issue number2
DOIs
Publication statusPublished - 15 Jul 2008

Scopus Subject Areas

  • Oncology
  • Cancer Research

User-Defined Keywords

  • ADAMTS9
  • Chromosome 3, metastasis
  • Nasopharyngeal carcinoma
  • Tumor suppressor gene

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