Yanrong Zhao

Abstract Heart development protein with EGF-like domains 1 (HEG1) plays critical roles in embryo development and angiogenesis, which are closely related to tumor progression. However, the role of HEG1 in hepatocellular carcinoma (HCC) remains unknown. In the present study, we explored the clinical significance, biological function and regulatory mechanisms of HEG1 in HCC and found that HEG1 is significantly up-regulated in HCC cell lines and primary tumor samples. Additionally, high HEG1 expression is correlated with aggressive clinicopathological features. Patients with high HEG1 expression had shorter overall survival (OS) and disease-free survival (DFS) than those with low HEG1 expression, which indicated that HEG1 is an independent factor for poor prognosis. Lentivirus-mediated HEG1 overexpression significantly promotes HCC cell migration, invasion and epithelial–mesenchymal transition (EMT) in vitro and promotes intrahepatic metastasis, lung metastasis and EMT in vivo. Opposing results are observed when HEG1 is silenced. Mechanistically, HEG1 promotes β-catenin expression and maintains its stability, leading to intracellular β-catenin accumulation, β-catenin nuclear translocation and Wnt signaling activation. Loss- and gain-of-function assays further confirmed that β-catenin is essential for HEG1-mediated promotion of HCC invasion, metastasis and EMT. In conclusion, HEG1 indicates poor prognosis; plays important roles in HCC invasion, metastasis and EMT by activating Wnt/β-catenin signaling; and can serve as a potentially valuable prognostic biomarker and therapeutic target for HCC.

Abstract Background & Aims BCAT 1 initiates the catabolism of branched‐chain amino acids. Here, we investigated the function of BCAT 1 and its transcriptional regulatory mechanism in hepatocellular carcinoma ( HCC ). Methods RNASeq was used to evaluate BCAT 1 mRNA levels in HCC and normal matched specimens. After the exogenous expression of BCAT 1 in BEL ‐7404 cells and the suppression of endogenous BCAT 1 expression with sh RNA in HepG2 cells, the cell proliferation, clone‐forming ability and cell‐cycle changes were measured with MTT assay, colony‐forming assay and flow cytometry respectively. A xenograft model was used to investigate the effect of BCAT 1 on cancer growth in vivo . Chromatin immunoprecipitation and luciferase reporter technologies were used to confirm the transcriptional regulation of the BCAT 1 gene by MYC . The expression of the BCAT 1 and MYC proteins in 122 HCC tissues was determined with an immunohistochemical analysis. Results BCAT 1 mRNA was clearly increased in HCC tissues and hepatomas. The ectopic expression of BCAT 1 in BEL ‐7404 cells enhanced their proliferation, clone formation, tumourigenic properties, S–G 2 /M phase transition and chemoresistance to cisplatin. The suppression of BCAT 1 expression in HepG2 cells significantly inhibited their proliferation, clone formation, and S–G 2 /M phase transition and caused their chemosensitization to cisplatin. MYC affected the transcriptional regulation of BCAT 1. Clinical data showed that BCAT 1 expression correlated with a significantly poorer prognosis. Conclusion BCAT 1 plays a pathogenic role in HCC by causing cell proliferation and chemoresistance. The MYC transcription factor is involved in regulating the transcriptional activity of BCAT 1. BCAT 1 expression has prognostic significance for the survival of patients with HCC .

The therapeutic potential of baicalein against hepatoma cells was evaluated in vitro and in vivo. In cell viability assays, baicalein showed significant cytotoxicity against the hepatocellular carcinoma cell lines H22, Bel-7404, and Hep G2 and moderate cytotoxicity against immortalized human hepatocytes. Baicalein induced G0/G1-phase arrest in hepatocellular carcinoma cells, inhibited AKT, and promoted the degradation of β-catenin and cyclin D1 without activation of GSK-3β. Furthermore, baicalein significantly inhibited H22 xenograft tumor growth without causing obvious adverse effects on weight or liver and spleen weight indexes in ICR mice. Immunohistochemical analysis showed that the inhibition of tumor growth in baicalein-treated mice was associated with decreased AKT, β-catenin, and cyclin D1 expression ex vivo. Our data indicate that baicalein might regulate cyclin D1 transcription via a β-catenin-dependent mechanism, leading to cell cycle arrest at G0/G1 phase and impaired cancer cell proliferation. These results suggest that baicalein is a potential candidate for the treatment of hepatocellular carcinoma.

Tumour metastasis is the main cause of postoperative tumour recurrence and mortality in patients with hepatocellular carcinoma (HCC), but the underlying mechanism remains unclear. Accumulating evidence has demonstrated that programmed cell death 10 (PDCD10) plays an important role in many biological processes. However, the role of PDCD10 in HCC progression is still elusive. In this study, we aimed to explore the clinical significance and molecular function of PDCD10 in HCC. PDCD10 is significantly upregulated in HCC, which also correlates with aggressive clinicopathological characteristics and predicts poor prognosis of HCC patients after liver resection. High PDCD10 expression promotes HCC cell proliferation, migration, and invasion in vitro and tumour growth, metastasis in vivo. In addition, PDCD10 could facilitate epithelial-to-mesenchymal transition (EMT) of HCC cells. In terms of the mechanism, PDCD10 directly binds to the catalytic subunit of protein phosphatase 2A (PP2Ac) and increases its enzymatic activity, leading to the interaction of YAP and dephosphorylation of the YAP protein. This interaction contributes to YAP nuclear translocation and transcriptional activation. PP2Ac is necessary for PDCD10-mediated HCC progression. Knocking down PP2Ac abolished the tumour-promoting role of PDCD10 in the migration, invasion and EMT of HCC. Moreover, a PP2Ac inhibitor (LB100) could restrict tumour growth and metastasis of HCC with high PDCD10 expression. Collectively, PDCD10 promotes EMT and the progression of HCC by interacting with PP2Ac to promote YAP activation, which provides new insight into the mechanism of cancer metastasis. PDCD10 may be a potential prognostic biomarker and therapeutic target for HCC.