Proliferation inhibition and differentiation induction of hepatic cancer stem cells by knockdown of BC047440: A potential therapeutic target of stem cell treatment for hepatocellular carcinoma

Abstract

Recent findings suggest that clinical hepatocellular carcinoma (HCC) progression is driven by hepatic cancer stem cells (HCSCs) through their capacity for self-renewal, generation of heterogeneous lineages of cancer cells, resistance to chemotherapy and their ability to divide limitlessly, which may contribute to the failure of existing therapies to consistently eradicate malignant tumors. Therefore, HCSC-directed therapeutic approaches might represent strategies to improve clinical HCC therapy. In previous studies, we showed that BC047440 was found to play a critical role in mediating HCC cell proliferation. The present study sought to determine whether BC047440 is involved in maintaining HCSC malignant behavior (including proliferation and differentiation). We demonstrated that BC047440 expression was markedly upregulated in HCSCs. Furthermore, we inhibited BC047440 in HCSCs using short hairpin RNA (shRNA). The effects of BC047440 on proliferation and differentiation were investigated. We also analyzed the involvement of critical molecular events known to regulate the proliferation and the differentiation machinery. Excluding apoptosis-related effects, we found that BC047440 inhibition resulted in enhanced cell proliferation through enhancing cytoplasmic accumulation of nuclear factor-κB (NF-κB) with a concomitant decrease in the nuclear fraction. BC047440 inhibition also resulted in inducing HCSC differentiation into hepatocytes. Furthermore, following downregulation of BC047440, the level of hepatocyte nuclear factor 4α (HNF4α) increased. Finally, tumorigenicity suppression following BC047440 depletion was confirmed in a nude mouse model. In conclusion, our findings indicate that BC047440 plays an important role in the proliferation and differentiation of HCSCs and may represent a novel therapeutic target for the treatment of HCC.

The emergence of long non-coding RNAs in the tumorigenesis of hepatocellular carcinoma

“…Therefore, HCSC-directed therapeutic approaches might represent strategies to improve clinical HCC therapy [78]. Future studies might aim to determine whether lncRNA is involved in maintaining HCSC malignant behavior (including proliferation and differentiation).…”

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

“…An all-trans retinoic acid was combined with conventional chemotherapy and used to treat patients with acute promyelocytic leukaemia, with successful induction of differentiation [110,111]. Recent studies have demonstrated that induction of differentiation of hepatic carcinoma stem cells by down-regulation of BC047440 (a gene involved in cancer growth and proliferation) suppressed the tumorigenic potential of hepatic carcinoma stem cells both in vivo and in vitro [112,113]. Also, Zieker and co-workers reported the induced differentiation of gastric carcinoma stem cells (CD44þ cells) by knocking-down phosphoglycerate kinase 1 (a metabolic enzyme responsible for cancer cell invasion and dissemination) using shRNA.…”

“…Inhibit the switching of stem cell like properties of cancer cells and prevent CSC generation [200][201][202] Differentiation Switching on metabolic pathways associated with cell maturation Make the CSCs more sensitive to conventional therapies and killed them completely [112][113][114][115] Metabolic pathways…”

Long non-coding RNAs and genes contributing to the generation of cancer stem cells in hepatocellular carcinoma identified by RNA sequencing analysis

“…The process of transformation of HCC cells to hepatocellular carcinoma stem cells (HCSCs) is associated with the initiation, progression, metastasis and poor prognosis of HCC (21,22).…”