Mammalian‐enabled (MENA) protein enhances oncogenic potential and cancer stem cell‐like phenotype in hepatocellular carcinoma cells

Abstract

Mammalian‐enabled ( MENA ) protein is an actin‐regulatory protein that influences cell motility and adhesion. It is known to play a role in tumorigenicity of hepatocellular carcinoma ( HCC ) but the underlying molecular mechanism remains unknown. This study aimed to investigate the oncogenic potential of MENA and its capacity to regulate cancer stem cell ( CSC )‐like phenotypes in HCC cells. Real‐time‐ PCR and western blot were used to assess mRNA and protein levels of target genes in human HCC tissue specimens and HCC cell lines, respectively. Stable MENA ‐overexpressing HCC cells were generated from HCC cell lines. Transwell cell migration and colony formation assays were employed to evaluate tumorigenicity. Ectopic expression of MENA significantly enhanced cell migration and colony‐forming ability in HCC cells. Overexpression of MENA upregulated several hepatic progenitor/stem cell markers in HCC cells. A high MENA protein level was associated with high mRNA levels of MENA , CD 133, cytokeratin 19 ( CK 19), and epithelial cell adhesion molecule (Ep CAM ) in human HCC tissues. Overexpression of MENA enhanced epithelial‐to‐mesenchymal transition ( EMT ) markers, extracellular signal‐regulated kinases ( ERK ) phosphorylation, and the level of β‐catenin in HCC cells. This study demonstrated that overexpression of MENA in HCC cells promoted stem cell markers, EMT markers, and tumorigenicity. These effects may involve, at least partially, the ERK and β‐catenin signaling pathways.

The identification and preliminary study of lncRNA TUG1 and its related genes in hepatocellular carcinoma

“…Researchers have demonstrated that NCAPG is associated with the growth of hepatoma cells, apoptosis, and epithelial mesenchymal transformation (EMT) [24]; NAP1L1 was found to be a nucleosome assembly protein in response to nucleosome remodelling through CSB protein and chromatin remodelling [25], promoting tumour progression as a chromatin regulatory factor in liver cancer [26]; PEA15, an essential prognostic marker for HCC, is involved in negative regulation of apoptosis signalling pathway mediated by death receptor, thereby inhibiting apoptosis of hepatoma cells. In addition, PEA15 also participates in transmembrane receptor protein tyrosine kinase signalling pathway, which mediates cell communication and promotes the migration of liver cancer cells, and the high level of ENAH expression promotes the occurrence and metastasis of liver cancer [27][28][29].…”

“…We found that TUG1 target genes NCAPG, VGLL4, HMGN4, PIGC, MCM6, NAP1L1, PEA15, GLS, HMGB2, PEA15, and ENAH were positively correlated with tumour stages (p < 0.05), suggesting that these target genes not only play a role in the development of liver cancer but also participate in tumour progression. For example, MCM6, PEA15, RACGAP1, and ENAH have been reported to promote the metastasis of HCC [17,[20][21][22][23][24][25][26][27][28][29][30]. The diagnostic effect analysis shows that TUG1 and its target genes have higher diagnostic efficacy than the traditional marker AFP in clinics, so further clinical trials are needed.…”

Scorpion inhibits epithelial–mesenchymal transition and metastasis of hepatocellular carcinoma

“…26 On the other hand, HCC cells can also get stem cell properties through EMT and have the ability of self-renewal and differentiation eventually to form a new metastasis. 27,28 Now many kinds of methods for the treatment of HCC may even induce EMT process of HCC to metastasis faster while slowing tumor growth. So, EMT is one of the important aspects for the prevention and control of HCC, and the inhibition of EMT has important therapeutic value in the treatment of HCC.…”

Emerging Regulatory Mechanisms Involved in Liver Cancer Stem Cell Properties in Hepatocellular Carcinoma

“…Park et al (2016) recently reported synergistic interactions between CD44 and TGF-β1 in EMT induction and CSC properties through the AKT/GSK-3β/β-catenin pathway in HCC cells. Moreover, Hu et al (2017) found that overexpression of mammalianenabled protein in HCC cells facilitated stem cell markers, EMT markers, and tumorigenicity through the extracellular signalregulated kinase (ERK) and β-catenin signaling pathways. In addition, it was confirmed that Aurora Kinase A (AURKA), an oncogene involved in tumor development, can induce the EMT process and CSC properties through the PI3K/Akt pathway; silencing AURKA inhibits radiation-enhanced cell invasiveness of HCC (Chen et al, 2017).…”