Knockdown of RARB2 identifies a dual role in cancer

Abstract

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.

Methylated circulating tumor DNA in blood: power in cancer prognosis and response

“…RARb2 , a retinoic acid receptor, has a complex role in regulating cell proliferation, and although it generally plays a role in tumor suppression ( Yang et al . 2002 ), tumor promotion effects have also been described ( Pappas et al . 2011 ).…”

Molecular Pathways: Current Role and Future Directions of the Retinoic Acid Pathway in Cancer Prevention and Treatment

“…A statistically significant restoration of RARβ expression and reduction of metaplasia were found in the 9-cis-RA group when compared to placebo (46). A recent study found a dual growth promoting and repressive role for RARβ2 in lung cancer cells, which may help explain the inconsistent results observed in clinical trials (47). …”

Retinoids induce cellular senescence in breast cancer cells by RAR-β dependent and independent pathways: Potential clinical implications (Review)

“…RARβ2 is expressed in normal MECs, but is lost in most breast cancer cells and in most premalignant lesions and tumors, suggesting its tumor suppressor role ( 39 ). Activation of RARβ2 by retinoids or by epigenetic approaches, as well as by gene transduction to cells lacking the receptor may lead to decreased proliferation and increased senescence ( 40 , 41 ). Previously, we have identified a novel RARβ (β5) isoform (GenBank: AC133141.2 and AC098477.2) which has an independent P3 promoter and appears to play a dominant negative role in RARβ signaling ( 42 ).…”

“…Thus, in a recent study it was shown that antisense oligonucleotides against RARβ2 reduced proliferation and caused apoptosis in 3 lung cancer cell lines, but had no effect in 2 other cell lines lacking RARβ2, suggesting that RARβ2 may not only suppress, but also promote proliferative activity of tumor cells and thus plays a role of proto-oncogene ( 41 ). RARβ isoforms may directly or indirectly cooperate with other RARs and RXRs, ER, and other nuclear receptors (PPARβ/γ, vitamin D, thyroid) and thus affect cellular responses to retinoids and rexinoids ( 9 , 41 ). In most breast carcinomas RARβ is downregulated by hypermethylation of its promoter and/or by alterations of chromatin structure ( 39 , 46 ).…”