Activated Notch signaling augments cell growth in hepatocellular carcinoma via up-regulating the nuclear receptor NR4A2

Abstract

Hepatocellular carcinoma (HCC) is one of the most malignant cancers. Conventional therapies are limited due to the human liver being such a unique organ and easily showing side-effects. The unclear molecular mechanisms are tough challenges for scientists searching for new and effective anti-HCC targeting drugs. We identified that the nuclear receptor NR4A2 is a novel oncogene in HCC progression. In this study, we show that NR4A2 and the notch recceptor Notch1 were expressed highly in primary HCC tissues and immortal HCC cells by using qPCR, western blot and immuno-histochemistry assays. Both genes were observed to stimulate HCC cell proliferation, anti-apoptosis and cell cycle arrest by using cell proliferation assays and FACS assays. We also observed that the four notch receptor subtypes (Notch1-4) displayed different effects on HCC cell growth. The over-expression of Notch1 by transiently transfecting the intracellular domain of Notch1 (ICN1, Notch1 active form) increased the expression of NR4A2, with the knockdown of Notch1 decreasing NR4A2. This indicates that NR4A2 is one of the Notch-mediated downstream genes. Moreover, both NR4A2 and Notch1 suppressed the expression of tumor suppressors p21 and p63. These findings support that Notch1/NR4A2 co-regulate HCC cell functions by playing oncogenic roles and regulating the associated downstream signaling pathways. Novel Notch1/NR4A2-mediated oncogenic signaling may provide us a great opportunity for anti-HCC drug development.

DEP domain containing 1 predicts prognosis of hepatocellular carcinoma patients and regulates tumor proliferation and metastasis

“…mRNA levels showed that alteration of DEPDC1 expression significantly changed the expression of most of the selected genes in the SMCC‐7721 cells (Figure D), including NR4A2, SEPP1, EDN2, LYPD3, MMP9, WNT6, RAC2, WNT1, PTCH1 and CTNNB1. The oncogenic function of RAC2, NR4A2, MMP9 WNT1, PTCH1 and CTNNB1 has been reported in HCC . These results indicated that DEPDC1 may activate specific oncogenic signal pathways to promote HCC cell proliferation and metastasis.…”

“…The oncogenic function of RAC2, NR4A2, MMP9 WNT1, PTCH1 and CTNNB1 has been reported in HCC. [17][18][19][20][21][22] These results indicated that DEPDC1 may activate specific oncogenic signal pathways to promote HCC cell proliferation and metastasis.…”

Surface decoration of selenium nanoparticles with curcumin induced HepG2 cell apoptosis through ROS mediated p53 and AKT signaling pathways

“…Hepatocellular carcinoma (HCC) is considered as one of the most common malignancies and ranks third in cancerassociated deaths around the world. [1][2][3][4] About 250 000 new cases of HCC increase every year, with nearly 6 000 000 deaths occurring. 5 The conventional therapies at the early stages of HCC include surgical restriction, interventional therapy, radiotherapy and radiofrequency ablation.…”

Cellular transformation by combined lineage conversion and oncogene expression

“…3d, top) are strongly upregulated, together with the canonical NOTCH target gene HES1 35 and the liver specific target NR4A2 36 . These results are consistent with the proposed role of the NOTCH pathway in liver tumorigenesis 36,37 . Thus, we show that CMT transduced HFs undergo senescence, whereas the proliferative phenotype of CMT-iHep cells is associated with gene expression changes in Wnt and NOTCH signaling pathways.…”