Oncogenic potential of retinoic acid receptor-gamma in hepatocellular carcinoma.
Retinoic acid receptors (RAR; alpha, beta, and gamma), 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 RARgamma were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARgamma promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARgamma enhanced, whereas downregulation of RARgamma expression by siRNA approach impaired, the effect of RA on inducing the expression of alpha-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARgamma contributed to liver cancer cell growth and transformation, we observed that RARgamma resided mainly in the cytoplasm of HCC cells, interacting with the p85alpha regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARgamma and p85alpha resulted in activation of Akt and NF-kappaB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARgamma plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-kappaB signaling pathways.
Yan
Ting-Dong
TD
Institute for Biomedical Research, Xiamen University; First Hospital of Xiamen, Xiamen, China.
Wu
Hua
H
Zhang
Hai-Ping
HP
Lu
Na
N
Ye
Ping
P
Yu
Feng-Hai
FH
Zhou
Hu
H
Li
Wen-Gang
WG
Cao
Xihua
X
Lin
Ya-Yu
YY
He
Jia-You
JY
Gao
Wei-Wei
WW
Zhao
Yi
Y
Xie
Lei
L
Chen
Jie-Bo
JB
Zhang
Xiao-Kun
XK
Zeng
Jin-Zhang
JZ
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D000509:alpha-Fetoproteins / Q000096:biosynthesis; D000097768:Retinoic Acid Receptor gamma
D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D000509:alpha-Fetoproteins; D000097768:Retinoic Acid Receptor gamma; C097353:AFP protein, human