Department of Pathology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10461, USA.
Clin Cancer Res. 2011 Feb 15;17(4):690-9. doi: 10.1158/1078-0432.CCR-10-1892. Epub 2010 Dec 10.
Because loss of Nkx2-8 increases lung cancer in the mouse, we studied suppressive mechanisms in human lung cancer.
NKX2-8 is located within 14q13.3, adjacent to its close relative TTF1/NKX2-1. We first analyzed LOH of 14q13.3 in forty-five matched human lung cancer and control specimens. DNA from tumors with LOH was then analyzed with high-density single-nucleotide polymorphism (SNP) arrays. For correlation with this genetic analysis, we quantified expression of Nkx2-8 and TTF1 mRNA in tumors. Finally, suppressive function of Nkx2-8 was assessed via colony formation assays in five lung cancer cell lines.
Thirteen of forty-five (29%) tumors had LOH. In six tumors, most adenocarcinomas, LOH was caused by gene amplification. The 0.8-Mb common region of amplification included MBIP, SFTA, TTF1, NKX2-8, and PAX9. In 4 squamous or adenosquamous cancers, LOH was caused by deletion. In three other tumors, LOH resulted from whole chromosome mechanisms (14(-), 14(+), or aneuploidy). The 1.2-Mb common region of deletion included MBIP, SFTA, TTF1, NKX2-8, PAX9, SLC25A21, and MIPOL1. Most tumors had low expression of Nkx2-8. Nevertheless, sequencing did not show NKX2-8 mutations that could explain the low expression. TTF1 overexpression, in contrast, was common and usually independent of Nkx2-8 expression. Finally, stable transfection of Nkx2-8 selectively inhibited growth of H522 lung cancer cells.
14q13.3, which contains NKX2-8, is subject to both amplification and deletion in lung cancer. Most tumors have low expression of Nkx2-8, and its expression can inhibit growth of some lung cancer cells.
由于 Nkx2-8 的缺失会导致小鼠肺癌的发生，因此我们研究了其在人类肺癌中的抑制机制。
NKX2-8 位于 14q13.3 上，紧邻其密切相关的 TTF1/NKX2-1。我们首先分析了 45 对匹配的人类肺癌和对照标本中 14q13.3 的 LOH。然后，我们使用高密度单核苷酸多态性 (SNP) 芯片分析肿瘤中存在 LOH 的 DNA。为了与这项遗传分析相关联，我们定量分析了肿瘤中 Nkx2-8 和 TTF1 mRNA 的表达。最后，我们在 5 种肺癌细胞系中通过集落形成实验评估了 Nkx2-8 的抑制功能。
在 45 例肿瘤中，有 13 例（29%）发生了 LOH。在 6 例腺癌中，大多数肿瘤的 LOH 是由基因扩增引起的。0.8Mb 的常见扩增区域包括 MBIP、SFTA、TTF1、NKX2-8 和 PAX9。在 4 例鳞癌或腺鳞癌中，LOH 是由缺失引起的。在另外 3 例肿瘤中，LOH 是由全染色体机制（14(-)、14(+)或非整倍体）引起的。1.2Mb 的常见缺失区域包括 MBIP、SFTA、TTF1、NKX2-8、PAX9、SLC25A21 和 MIPOL1。大多数肿瘤中 Nkx2-8 的表达水平较低。然而，测序并未发现能解释低表达的 NKX2-8 突变。相比之下，TTF1 的过表达很常见，而且通常独立于 Nkx2-8 的表达。最后，稳定转染 Nkx2-8 选择性抑制了 H522 肺癌细胞的生长。
14q13.3 包含 NKX2-8，在肺癌中既发生扩增又发生缺失。大多数肿瘤中 Nkx2-8 的表达水平较低，其表达可以抑制一些肺癌细胞的生长。
