Sorafenib, a multikinase inhibitor, is a new standard treatment for patients with advanced hepatocellular carcinoma (HCC). However, resistance to this regimen is frequently observed in clinical practice, and the molecular basis of this resistance remains largely unknown. Herein, the antitumor activity of sorafenib was assessed in 16 patient-derived xenograft (PDX) models of HCC. Gene expression analysis was conducted to identify factors that promote sorafenib resistance. Quantitative RT-PCR and immunoblotting were used to determine gene expression and activation of signaling pathways. Cell proliferation, clone formation, and transwell assays were conducted to evaluate drug-sensitivity, proliferation, and invasiveness, respectively. Kaplan-Meier analysis was used to evaluate the predictive power of biomarkers for sorafenib response. Differential gene expression analysis suggested that sorafenib resistance correlated with high karyopherin subunit alpha 3 (KPNA3) expression. Overexpression of KPNA3 in HCC cells enhanced tumor cell growth and invasiveness. Interestingly, KPNA3 was found to trigger epithelial-mesenchymal transition (EMT), a key process mediating drug resistance. On a mechanistic level, KPNA3 increased phosphorylation of AKT, which then phosphorylated ERK, and ultimately promoted TWIST expression to induce EMT and sorafenib resistance. Moreover, retrospective analysis revealed that HCC patients with low KPNA3 expression had remarkably longer survival after sorafenib treatment. Finally, we have identified a novel KPNA3-AKT-ERK-TWIST signaling cascade that promotes EMT and mediates sorafenib resistance in HCC. These findings suggest that KPNA3 is a promising biomarker for predicting patient responsiveness to sorafenib. Targeting KPNA3 may also contribute to resolving sorafenib resistance in HCC.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality and carries a dismal prognosis. The present study aimed to identify the tumour-suppressive role and clinical implications of PTPN13 in HCC progression. We tested the effects of PTPN13 expression in proliferation, invasion, epithelial-mesenchymal transition and associated pathways in HCC cell lines in vitro. Furthermore, its clinical relevance was evaluated in a tissue microarray analysis of samples from 282 HCC patients. Various HCC cell lines expressed relatively low PTPN13 protein levels in vitro. PTPN13 overexpression significantly inhibited the progression of HCC cells, possibly by inhibiting epithelial-mesenchymal transition through inactivation of the EGFR/ERK signalling pathway. Tissue microarray analysis revealed that high PTPN13 expression was correlated with a favourable prognosis in postoperative HCC patients. This study demonstrated the tumour suppressor, PTPN13, as an alternative therapeutic target for HCC.

No abstract

Accumulating data suggest that metadherin (MTDH) may function as an oncogene. Our previous study showed that MTDH promotes hepatocellular carcinoma (HCC) metastasis via the epithelial-mesenchymal transition. In this study, we aim to further elucidate how MTDH promotes HCC metastasis. Using Co-immunoprecipitation (co-IP) and mass spectrometry, we found that MTDH can specifically bind to protein arginine methyltransferase 5 (PRMT5). Further functional assays revealed that PRMT5 overexpression promoted the proliferation and motility of HCC cells and that knockout of PRMT5 impeded the effect of MTDH. The immunohistochemistry assay/tissue microarray results showed that when MTDH was overexpressed in HCC cells, PRMT5 translocated from the nucleus to the cytoplasm, with the subsequent translocation of β-catenin from the cytoplasm to the nucleus and upregulation of the WNT–β-catenin signaling pathway. Further in vivo experiments suggested that PRMT5 and β-catenin played a pivotal role in MTDH-mediated HCC metastasis. We therefore concluded that the MTDH–PRMT5 complex promotes HCC metastasis by regulating the WNT–β-catenin signaling pathway.

Background and Aims: Heat shock factor (HSF4) plays a vital role in carcinogenesis and tumour progression. However, its clinical significance implications in hepatocellular carcinoma (HCC) remained elusive.Methods: RT-PCR and western blot were used to detect the HSF4 expression levels in HCC cells and tissues. Immunohistochemistry staining was performed on a tissue microarray containing 104 HCC patients received radical resection. In vitro effects of HSF4 on proliferation, migration and invasion were determined by colony formation and transwell assays in HCCLM3, Huh7, MHCC97L and SMMC7721 cells. Epithelialmesenchymal transition (EMT) was identified by RT-PCR, WB and immunofluorescence in HCCLM3 and MHCC97L cells. AKT pathway activation was detected by WB and dual luciferase report system in HCCLM3 and MHCC97L cells.Results: HSF4 expression was higher in primary HCC tissues derived from recurrent patients, and positively correlated with invasiveness potentials of cell lines. Clinically,

In this work, we synthesized PtM (M = Mn, Co) nanofascicles which are formed by a bundle of nanowires. Specially, each nanowire is ultrathin with a diameter of ~2.0 nm....

Previous research suggests that far upstream element-binding protein 1 (FUBP1) plays an important role in various tumors including epatocellular carcinoma (HCC). However, the role of FUBP1 in liver cancer remains controversial, and the regulatory pathway by FUBP1 awaits to be determined. This study aims to identify the role of FUBP1 in HCC progression. Our result shows that the high level of FUBP1 expression in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion, and metastasis by activating transforming growth factor-β (TGF-β)/Smad pathway and enhancing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Inhibitor of Thrombospondin-1 (LSKL) could inhibit HCC proliferation and invasion in vitro and in vivo by blocking the activation of TGF-β/Smad pathway mediated by thrombospondin-1 (THBS1). Our study identified the critical role of FUBP1-THBS1-TGF-β signaling axis in HCC and provides potentially new therapeutic modalities in HCC.

Background Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer-related mortality in China with increasing incidence. This study is designed to explore early genetic changes implicated in HCC tumorigenesis and progression by whole-exome sequencing. Methods We firstly sequenced the whole exomes of 5 paired hepatitis B virus-related early-stage HCC and peripheral blood samples, followed by gene ontological analysis and pathway analysis of the single-nucleotide variants discovered. Then, the mutations of high frequency were further confirmed by Sanger sequencing. Results We identified a mutational signature of dominant T:A>A:T transversion in early HCC and significantly enriched pathways including ECM-receptor interaction, axon guidance, and focal adhesion and enriched biological processes containing cell adhesion, axon guidance, and regulation of pH. Eight genes, including MUC16, UNC79, USH2A, DNAH17, PTPN13, TENM4, PCLO, and PDE1C, were frequently mutated. Conclusions This study reveals a mutational profile and a distinct mutation signature of T:A>A:T transversion in early-stage HCC with HBV infection, which will enrich our understanding of genetic characteristics of the early-stage HCC.