Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma

Abstract

Retinoic acid receptors (RAR; α, β, and γ), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RARγ were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARγ promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARγ enhanced, whereas downregulation of RARγ expression by siRNA approach impaired, the effect of RA on inducing the expression of α-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARγ contributed to liver cancer cell growth and transformation, we observed that RARγ resided mainly in the cytoplasm of HCC cells, interacting with the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARγ and p85α resulted in activation of Akt and NF-κB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARγ plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-κB signaling pathways. Cancer Res; 70(6); 2285-95. ©2010 AACR.

RARγ Downregulation Contributes to Colorectal Tumorigenesis and Metastasis by Derepressing the Hippo–Yap Pathway

“…Of note, we previously reported that RARg, rather than RARa and RARb, has a unique cytoplasmic localization in many cancer cell types (7). Cytoplasmic accumulation of RARg in HCC cells plays an oncogenic role via nongenomic activation of Akt/NF-kB signaling (10). We here further revealed a surprising nongenomic role of RARg in colorectal cancer, wherein RARg nongenomically regulates the Hippo-Yap pathway via interacting with and sequestering Yap in the cytoplasm.…”

“…Recent evidence indicated the critical roles of aberrant expression of RARg in tumorigenesis (8,10,13). However, the expression profile and role of RARg in colorectal cancer remain unknown.…”

“…RARg is also suggested to suppress Ras-induced squamous cell carcinoma (13), suggesting RARg may act as a tumor suppressor in tumorigenesis. Conversely, RARg is often overexpressed in many human cancers, such as HCC and cholangiocarcinoma, and functions as a tumor promotor to drive cancer cell growth and metastasis (8,10). Combined, these data indicate that RARg is involved in the regulation of tumorigenesis and its potential functions depend on different cancer types and a cell-specific context.…”

“…We recently also reported that RARg nongenomically activates the PI3K/Akt and NF-kB signaling pathway through its interaction with the p85a regulatory subunit of PI3K in hepatocellular carcinoma (HCC; ref. 10).…”

Oncogenic Activity of Retinoic Acid Receptor γ Is Exhibited through Activation of the Akt/NF-κB and Wnt/β-Catenin Pathways in Cholangiocarcinoma

“…RAR␥ can activate cellular SRC (c-SRC) in the cytoplasm through hormone-dependent direct binding to c-SRC, a process required for neuritogenesis (14). In particular, a recent report revealed that RAR␥ plays an oncogenic role via activation of the Akt/NF-B pathway in the progression of HCC (15). However, the expression profile of RAR␥ protein and its roles and mechanisms in CCA progression remain unknown.…”