Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma

Tayebi, H.M. El; Abdelaziz, Ahmed Ihab

doi:10.3748/wjg.v22.i9.2668

Cited by 12 publications

(9 citation statements)

References 99 publications

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“…Exploring the specific mechanism of hepatocarcinogenesis and its early metastasis is of great value for early diagnosis and improving prognosis of HCC. Previous studies on the pathogenesis and development of HCC mostly focus on the traditional protein coding genes, which mainly involve the regulation of genetics, epigenetics, and related signaling pathways . With the development of high‐throughput sequencing technology, it has been revealed that the non‐coding RNA (ncRNA) accounted for more than 95% of the human genome, and the complex interaction between the protein encoding RNA and functional ncRNA played an important role in the occurrence and development of HCC .…”

Section: Introductionmentioning

confidence: 99%

LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR‐24‐3p

Fan

Zeng

et al. 2018

J of Cellular Biochemistry

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Cancer susceptibility candidate 2 (CASC2), a recently discovered long non-coding RNA (lncRNA), was confirmed to play numerous roles in several human cancers. However, the involvement and concrete mechanism of CASC2 in hepatocellular carcinoma (HCC) still need to be further elucidated. The relative expressions of CASC2 and miR-24-3p in HCC tissue and cell lines were determined by quantitative real-time PCR (qRT-PCR). The effects of CASC2 and miR-24-3p on HCC cells were further assessed via cell viability and apoptosis. In vivo tumorigenesis assay was performed to verify the inhibition effect of CASC2 on the tumor growth and further clarify the important role of miR-24-3p in this mechanism. Compared with the paired normal tissues, the relative expression of CASC2 significantly reduced in the HCC tissues, while miR-24-3p as determined by qRT-PCR obviously increased in the HCC tissues. This observation was also found in HCC cell lines. Meanwhile, the expression of CASC2 was negatively related to miR-24-3p expression in the HCC tissues (r = -0.804, P < 0.001). CASC2 could negatively regulate the expression of miR-24-3p in vitro. Moreover, CASC2 overexpression resulted in the growth inhibitory and apoptosis-inducing effects on HCC cells, but the up-regulation of miR-24-3p greatly eliminated the CASC2-induced effects. The tumorigenesis of HCC cells was restrained significantly by CASC2 overexpression as shown by decreased tumor volume and growth rate. However, miR-24-3p up-regulation rescued the inhibition of CASC2 on the tumor growth in tumor-bearing mice. LncRNA CASC2 inhibited the viability and induced the apoptosis of HCC cells through regulating miR-24-3p.

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Section: Introductionmentioning

confidence: 99%

LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR‐24‐3p

Fan

Zeng

et al. 2018

J of Cellular Biochemistry

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“…Multiple risk factors, such as chronic infection of hepatitis B and C viruses (HBV, HCV), alcohol abuse contribute to development of HCC [ 3 – 5 ]. Although the molecular mechanism for the pathogenesis of HCC has not been well described, mounting evidence has demonstrated the aberrant activation of cell signaling pathways such as AKT/mTOR, RAS/MAPK, Wnt/β-catenin, insulin-like growth factor (IGF), and nuclear factor-κB (NF-κB) were involved in the development of HCC [ 6 , 7 ]. In recent years, growing evidence has suggested that microRNAs (miRNAs) play a critical role in the progression, invasion, and angiogenesis of HCC [ 8 – 11 ].…”

Section: Introductionmentioning

confidence: 99%

RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma

Yang

Huang

et al. 2018

Oncotarget

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Hepatocellular carcinoma (HCC) is one of the common cancers worldwide, especially in developing countries. Although the chronic infections of hepatitis B and C viruses have been established as the etiological factors of HCC, the mechanism for the tumorigenesis and development of HCC is still unclear. The liver-specific microRNA-122 (miR-122), an established tumor-suppressor miRNA, is often down-regulated in HCC, while the underlying mechanism is not well understood. Here we report that the AU-rich element-binding factor AUF1 suppresses the expression of Dicer1, the type III RNase that is required for microRNA maturation, leading to the inhibited biogenesis of miR-122. Overexpression of AUF1 led to the decreased expression of Dicer1 and miR-122, while the level of the miR-122 precursor (pre-miR-122) was increased. On the other hand, siRNA of AUF1 (siAUF1) increased the levels of Dicer1 mRNA and miR-122, but it reduced the abundance of pre-miR-122. Consistent with the reported data, this study demonstrated that AUF1 and Dicer1 showed opposite expression pattern in both human HCC tissues and cell lines. In addition, AUF1 inhibited the expression of Dicer1 by interacting with the 3′ untranslated region (3′UTR) and coding region of DICER1 mRNA. Moreover, the knockdown of AUF1 by siRNA altered the expression of other miRNAs and promoted HCC cell death. In conclusion, AUF1 down-regulates the expression miR-122 by interacting with the 3′UTR and coding region of DICER1 mRNA and suppressing Dicer1 expression. The AUF1/Dicer1/miR-122 pathway might play a critical role in the development of HCC.

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“…The insulin-like growth factor (IGF) signalling pathway is another important pathway in the process of hepatocarcinogenesis: three IGF axis members are known to be involved in the development of HCC [45].…”

Section: Resultsmentioning

confidence: 99%

Metformin Counteracts HCC Progression and Metastasis Enhancing KLF6/p21 Expression and Downregulating the IGF Axis

Vacante

Senesi

Montesano

et al. 2019

International Journal of Endocrinology

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Background and Aims Hepatocellular carcinoma (HCC) is the common tumor of the liver. Unfortunately, most HCC seem to be resistant to conventional chemotherapy and radiotherapy. The poor efficacy of antitumor agents is also due, at least in part, to the inefficient drug delivery and metabolism exerted by the steatotic/cirrhotic liver that hosts the tumor. Thus, novel approaches in chemotherapy may be needed to improve the survival rate in patients with HCC. Metformin (METF) has been found to lower HCC risk; however, the mechanisms by which METF performs its anticancer activity are not completely elucidated. Previous studies have showed METF action on growth inhibition in the liver in a dose/time-dependent manner and its antitumor role by targeting multiple pathways. We investigated molecular effects of METF in an in vitro human hepatoma model (HepG2), studying cell cycle regulators, tumorigenesis markers, and insulin-like growth factor (IGF) axis regulation. Materials and Methods HepG2 cells were treated with METF (400 μM) for 24, 48, and 72 hours. METF action on cell cycle progression and cellular pathways involved in metabolism regulation was evaluated by gene expression analysis, immunofluorescence, and Western blot assay. Results By assessing HepG2 cell viability, METF significantly decreased growth cell capacity raising KLF6/p21 protein content. Moreover, METF ameliorated the cancer microenvironment reducing cellular lipid drop accumulation and promoting AMPK activity. The overexpression of IGF-II molecule and the IGF-I receptor that plays a main role in HCC progression was counteracted by METF. Furthermore, the protein content of HCC principal tumor markers, CK19 and OPN, linked to the metastasis process was significantly reduced by METF stimulus. Conclusion Our data show that METF could suppress HepG2 proliferation, through induction of cell cycle arrest at the G0/G1 phase. In addition, METF effect on the cancer microenvironment and on the IGF axis leads to the development of new METF therapeutic use in HCC treatment.

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Epigenetic regulation of insulin-like growth factor axis in hepatocellular carcinoma

Cited by 12 publications

References 99 publications

LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR‐24‐3p

LncRNA CASC2 inhibited the viability and induced the apoptosis of hepatocellular carcinoma cells through regulating miR‐24‐3p

RNA-binding protein AUF1 suppresses miR-122 biogenesis by down-regulating Dicer1 in hepatocellular carcinoma

Metformin Counteracts HCC Progression and Metastasis Enhancing KLF6/p21 Expression and Downregulating the IGF Axis

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