Knockdown of RARB2 identifies a dual role in cancer

Two chemoprevention trials have shown that retinoic acid (RA) may be harmful in patients at risk for lung cancer, and RA administration to this high-risk group results in RARB2 reactivation. Although RARB2 is thought to possess tumor suppressive activity, its expression has recently been correlated with poorer prognosis in patients with nonsmall cell lung cancer. We hypothesized that RARB2 expression is necessary for the growth and maintenance of the oncogenic phenotype in lung cancer cells in which RARB2 has not been inactivated. We tested various antisense oligodeoxynucleotides (ASO) against RARB2 in multiple lung cancer cell lines and used microarray technology to compare the patterns of gene expression following ASO treatment versus RA treatment in the A-549 lung cancer cell line. We show that ASO treatment reduces proliferation and causes apoptosis in 3 RARB2-expressing lung cancer cell lines but has no apparent effect in at least two other lung cancer cells lines having lost RARB2 expression or one normal lung RARB2-expressing cell line; we demonstrate a correlation between resulting RARB2 expression levels and cell growth; and identify transcriptional effects related to both RA and RARB2 signaling. In particular, five genes known to contribute to carcinogenesis or chemotherapeutic resistance are down-regulated following ASO treatment: three of these are up-regulated following RA treatment. This work demonstrates a dual role for RARB2 (tumor suppression and tumor promotion) and identifies a challenge with respect to using RARB2 as a target for treatment or prevention strategies.