Song Shumei, Guan Baoxiang, Men Taoyan, Hoque Ashraful, Lotan Reuben, Xu Xiao-Chun
Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Prev Res (Phila). 2009 Mar;2(3):274-80. doi: 10.1158/1940-6207.CAPR-08-0180. Epub 2009 Mar 3.
Retinoic acid receptor-beta2 (RAR-beta2) is a putative tumor suppressor gene in various cancers. To determine the underlying molecular mechanisms, we transfected RAR-beta2 cDNA into esophageal cancer TE-1 and TE-8 cells and found that RAR-beta2 suppressed tumor cell growth in vitro and tumor formation in nude mice in TE-8 cells, whereas the stable transfection of RAR-beta2 did not restore retinoid sensitivity or inhibit tumor formation in nude mouse in TE-1 cells. Molecularly, we revealed that RAR-beta2 antitumor activity was associated with expression and suppression of cyclooxygenase-2 (COX-2) in these tumor cell lines. Moreover, antisense RAR-beta2 cDNA induced COX-2 expression in TE-3 cells. Furthermore, when COX-2 expression is first blocked by using antisense COX-2 expression vector, the effect of RAR-beta2 is diminished in these tumor cells. In addition, we analyzed expression of RAR-beta2 and COX-2 mRNA in tissue specimens and found that RAR-beta2 expression is associated with low levels of COX-2 expression in esophageal cancer tissues. Induction of RAR-beta2 expression in oral leukoplakia tissues after the patients treated with 13-cis RA correlated with a reduction in COX-2 expression and clinical response. Our findings indicate that some of RAR-beta2 antitumor activities are mediated by suppression of COX-2 expression in some of these esophageal cancer cells. After correlating antitumor effect of RAR-beta2 with COX-2 expression in the published studies, we also found the association. Thus, further studies will determine whether manipulation of COX-2 expression in different cancers can antagonize RAR-beta2 activity.
维甲酸受体-β2（RAR-β2）在多种癌症中被认为是一种肿瘤抑制基因。为了确定其潜在的分子机制，我们将RAR-β2 cDNA转染至食管癌TE-1和TE-8细胞中，发现RAR-β2在体外抑制肿瘤细胞生长，并在TE-8细胞中抑制裸鼠体内肿瘤形成，而在TE-1细胞中稳定转染RAR-β2并不能恢复类维生素A敏感性或抑制裸鼠体内肿瘤形成。从分子水平来看，我们发现RAR-β2的抗肿瘤活性与这些肿瘤细胞系中环氧合酶-2（COX-2）的表达及抑制有关。此外，反义RAR-β2 cDNA在TE-3细胞中诱导COX-2表达。而且，当使用反义COX-2表达载体首先阻断COX-2表达时，RAR-β2在这些肿瘤细胞中的作用会减弱。另外，我们分析了组织标本中RAR-β2和COX-2 mRNA的表达，发现食管癌组织中RAR-β2表达与低水平的COX-2表达相关。13-顺式维甲酸治疗后的口腔白斑组织中RAR-β2表达的诱导与COX-2表达的降低及临床反应相关。我们的研究结果表明，RAR-β2的某些抗肿瘤活性是通过抑制某些食管癌细胞中COX-2的表达介导的。在已发表的研究中将RAR-β2的抗肿瘤作用与COX-2表达相关联后，我们也发现了这种关联。因此，进一步的研究将确定在不同癌症中操纵COX-2表达是否能拮抗RAR-β2的活性。
