No abstract

Sorafenib is the first-line chemotherapeutic therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib resistance significantly limits its therapeutic efficacy, and the mechanisms underlying resistance have not been fully clarified. Here we report that a circular RNA, circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells), plays a significant role in sorafenib resistance in HCC. We found that circRNA-SORE is upregulated in sorafenib-resistant HCC cells and depletion of circRNA-SORE substantially increases the cell-killing ability of sorafenib. Further studies revealed that circRNA-SORE binds the master oncogenic protein YBX1 in the cytoplasm, which prevents YBX1 nuclear interaction with the E3 ubiquitin ligase PRP19 and thus blocks PRP19-mediated YBX1 degradation. Moreover, our in vitro and in vivo results suggest that circRNA-SORE is transported by exosomes to spread sorafenib resistance among HCC cells. Using different HCC mouse models, we demonstrated that silencing circRNA-SORE by injection of siRNA could substantially overcome sorafenib resistance. Our study provides a proof-of-concept demonstration for a potential strategy to overcome sorafenib resistance in HCC patients by targeting circRNA-SORE or YBX1.

A B S T R A C TIn most cases, sorafenib-resistant HCC cells exhibit significant mesenchymal phenotype and stemness features. In this context, tumor cells might undergo cell fate transition in response to sorafenib or other targeted drugs in the presence or absence of genetic mutations. Therefore, understanding the major characteristics of drug-resistant cells state helps to discover new treatments that overcome drug resistance. To note, little is known about the metabolic or microenvironmental aspects of the certain tumor cell states beyond the genome. This review mainly focuses on the underlying mechanisms of acquired sorafenib resistance based on CSCs and EMT models, which explain tumor heterogeneity and have been considered the major cause of secondary sorafenib resistance. In particular, it discusses how the tumor microenvironment and tumor metabolism regulate cell stemness, mesenchymal state, and sorafenib resistance through epigenetic regulations, and provides reliable targets that might have synergetic effect with sorafenib.

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy as a result of complex genetic and epigenetic alterations. HCC is characterized by a clear gender disparity for which there is lack of a clear mechanistic understanding. Androgen receptor (AR) is thought to be critical for such bias. Meanwhile, the potential function of circular RNA (circRNA), regulated by RNA editing enzyme, remained largely unknown in malignancy till now. By utilizing circRNA microarray survey coupled with in vitro analysis, we analyzed the influence of AR on circRNA expression in HCC. Our results indicated that AR could suppress circRNA expression by upregulating ADAR1 p110. Such effect is because AR served as a transcriptional activator of ADAR1 promoter. More significantly, data collected from our center strongly suggest that ADAR1 expression can effectively predict HCC patients’ prognosis and an abnormal overexpression of ADAR1 is positively correlated with AR in HCC. In addition, we found CircARSP91 (hsa_circ_0085154), one of the circRNAs downregulated by AR in an ADAR1-dependent manner, could inhibit HCC tumor growth both in vitro and in vivo. These findings highlight the fact that AR as a contributing factor for gender disparity in HCC can cause complex consequences though regulation of circRNA expression. Better understanding of the roles of circRNA during HCC initiation and progression will provide a novel angle to develop potential HCC therapies.

Hepatocellular carcinoma (HCC) is one of the most common malignant cancers and currently the third leading cause of cancer-related deaths, worldwide. Epithelial–mesenchymal transition (EMT) plays a major role in HCC progression. In this study, we first found that the expression of E74-like ETS transcription factor 3 (ELF3), a member of the E-twenty-six family of transcription factors, was increased in HCC tissues, and that ELF3 overexpression was associated with poor prognoses for HCC patients. Gain-of-function and loss-of-function studies revealed that increased ELF3 expression promoted HCC cell proliferation, migration, and invasion, while these processes were inhibited when ELF3 was silenced. Additionally, ELF3 was found to promote EMT, which we demonstrated through decreased E-cadherin expression and increased N-cadherin and fibronectin expression. ELF3 knockdown reversed EMT via repressing ZEB1 expression through miR-141-3p upregulation. Chromatin immunoprecipitation assays revealed that ELF3 bound to the miR-141-3p promoter, suppressing miR-141-3p expression. Taken together, our data show that ELF3 repressed E-cadherin and promoted EMT in HCC cells by suppressing miR-141-3p, thereby activating ZEB1. Thus, ELF3 may be a potential prognostic biomarker and/or therapeutic target for HCC.

Dual-specificity phosphatase-1 (DUSP1/MKP1), as a member of the threoninetyrosine dual-specificity phosphatase family, was first found in cultured murine cells. The molecular mechanisms of DUSP1-mediated extracellular signalregulated protein kinases (ERKs) dephosphorylation have been subsequently identified by studies using gene knockout mice and gene silencing technology. As a protein phosphatase, DUSP1 also downregulates p38 MAPKs and JNKs signaling through directly dephosphorylating threonine and tyrosine. It has been detected that DUSP1 is involved in various functions, including proliferation, differentiation, and apoptosis in normal cells. In various human cancers, abnormal expression of DUSP1 was observed which was associated with prognosis of tumor patients. Further studies have revealed its role in tumorigenesis and tumor progression. Besides, DUSP1 has been found to play a role in tumor chemotherapy, immunotherapy, and biotherapy. In this review, we will focus on the function and mechanism of DUSP1 in tumor cells and tumor treatment. Cancer Medicine Open Access 2062

Autophagy1 is a complex of adaptive cellular response that enhances cancer cell survival in the face of cellular stresses such as chemothery. Here we show that in human gallbladder carcinoma (GBC) cells lines, SGC-996 and GBC-SD, autophagy is induced by the DNA damaging agent 5-fluorouracil (5-FU). While in combination with the pre-treatment of chloroquine (CQ), a inhibitor of autophagy, the inhibition of 5-FU to the proliferation and viability of GBC cells was potentiated. Furthermore, 5-FU treatment resulted in a general increase of the apoptotic rate and G0/G1 arrest of GBC cells, and the effect was potentiated by CQ pre-treatment. Since 5-FU induced autophagy in GBC cells, and CQ inhibited autophagy, our findings suggest a possible mechanism that CQ inhibited 5-FU-induced autophagy, which modified the cytotoxicity of 5-FU. The combination therapy of CQ and 5-FU should be considered as an effective strategy for the treatment of gallbladder carcinoma.

In terms of the feasibility and safety, this study showed that ALPPS in the treatment of hepatocellular carcinoma with insufficient future liver remnant might be a double-edged sword, and careful patients selected was proposed. Too small of FLR/SLV, less than 30%, is not recommended for ALPPS in liver with cirrhosis.