Notch1 activation contributes to tumor cell growth and proliferation in human hepatocellular carcinoma HepG2 and SMMC7721 cells

Abstract

Notch signaling controls cellular differentiation and proliferation. Recent studies have shown that Notch signaling plays an important role in the carcinogenesis and progression of a growing number of malignant tumors. We investigated the effect of Notch1 activation on human hepatocellular carcinoma (HCC). In five human HCC cell lines, it was found that SMMC7721 had relatively high while HepG2 relatively low expression of Notch1 and the activity of Notch signaling. Notch1 activation by transfection of active intracellular region of Notch1 (ICN1) into HCC HepG2 cells enhanced cell growth and proliferation, including in vitro single cell colony formation, anchorage-independent proliferation, and in vivo tumorigenicity. Notch1 activation also promoted HepG2 cell cycle progression. Suppression of Notch1 activation by RNAi of Notch1 or by γ-secretase inhibitor (GSI) in HCC SMMC7721 cells decreased cell growth capability and blocked cell cycle progression. Moreover, it was found that suppression of Notch1 activation induced SMMC7721 cell apoptosis, as demonstrated by apoptosis assays. These findings indicate that Notch1 activation promotes human HCC cell growth and proliferation, which may contribute to the progression of this type of malignant carcinoma.

MDM2–MOF–H4K16ac axis contributes to tumorigenesis induced by Notch

“…According to previous reports of HCC [7,26] and breast cancer [27], Notch can both promote and suppress tumorigenesis. Responses to Notch signaling could be environment and cell-type dependent [28].…”

“…Notch signaling activity is closely related to the proliferation and migration of HCC and breast cancer cells [7,[23][24][25]. Notch signaling activation led to changes at the transcriptional level of numerous genes, and H4K16Q (a mutation to mimic the acetylation state of H4K16) could rescue some of these (Fig.…”

“…The luciferase assay was performed according to the protocol reported by Gao et al [7]. The whole cell lysates were tested using immunoblot assay with specific primary antibodies.…”

“…Following activation of the Notch pathway, the Notch intracellular domain (NIC) translocates to the nucleus to activate transcription of target genes [4]. Aberrant activation of the Notch pathway leads to various diseases including cancer [4,7]. Several studies previously showed that Notch signaling could be mediated through regulation of epigenetic modifications and indicated that this relationship could be a new target for cancer therapy [8,9].…”

“…The Notch pathway comprises a family of transmembrane receptors and ligands, modifiers and transcription factors [7]. Following activation of the Notch pathway, the Notch intracellular domain (NIC) translocates to the nucleus to activate transcription of target genes [4].…”