Yuelong Liang

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

Sorafenib, an orally-available kinase inhibitor, is the only standard clinical treatment against advanced hepatocellular carcinoma. However, development of resistance to sorafenib has raised concern in recent years due to the high-level heterogeneity of individual response to sorafenib treatment. The resistance mechanism underlying the impaired sensitivity to sorafenib is still elusive though some researchers have made great efforts. Here, we provide a systemic insight into the potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma depending on abundant previous studies and reports.

Circular RNA expression is suppressed by androgen receptor (AR)-regulated adenosine deaminase that acts on RNA (ADAR1) in human hepatocellular carcinoma

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.

The role of exosomes in hepatitis, liver cirrhosis and hepatocellular carcinoma

Exosomes are small vesicles that were initially thought to be a mechanism for discarding unneeded membrane proteins from reticulocytes. Their mediation of intercellular communication appears to be associated with several biological functions. Current studies have shown that most mammalian cells undergo the process of exosome formation and utilize exosome‐mediated cell communication. Exosomes contain various microRNAs, mRNAs and proteins. They have been reported to mediate multiple functions, such as antigen presentation, immune escape and tumour progression. This concise review highlights the findings regarding the roles of exosomes in liver diseases, particularly hepatitis B, hepatitis C, liver cirrhosis and hepatocellular carcinoma. However, further elucidation of the contributions of exosomes to intercellular information transmission is needed. The potential medical applications of exosomes in liver diseases seem practical and will depend on the ingenuity of future investigators and their insights into exosome‐mediated biological processes.

Cytoplasmic and/or nuclear expression of β-catenin correlate with poor prognosis and unfavorable clinicopathological factors in hepatocellular carcinoma: a meta-analysis.

Background The β-catenin is an important effector in WNT/β-catenin signaling pathway, which exerts a crucial role in the development and progression of hepatocellular carcinoma (HCC). Some researchers have suggested that the overexpression of β-catenin in cytoplasm and/or nucleus was closely correlated to metastasis, poor differentiation and malignant phenotype of HCC while some other researchers hold opposite point. So far, no consensus was obtained on the prognostic and clinicopathological significance of cytoplasmic/nuclear β-catenin overexpression for HCCs. Methods Systematic strategies were applied to search eligible studies in all available databases. Subgroup analyses, sensitivity analyses and multivariate analysis were performed. In this meta-analysis, we utilized either fixed- or random-effects model to calculate the pooled odds ratios (OR) and its 95% confidence intervals (CI). Results A total of 22 studies containing 2334 cases were enrolled in this meta-analysis. Pooled data suggested that accumulation of β-catenin in cytoplasm and/or nucleus significantly correlated with poor 1-, 3- and 5-year OS and RFS. Moreover, nuclear accumulation combined with cytoplasmic accumulation of β-catenin tended to be associated with dismal metastasis and vascular invasion while cytoplasmic or nuclear expression alone showed no significant effect. Besides, no significant association was observed between cytoplasmic and/or nuclear β-catenin expression and poor differentiation grade, advanced TNM stage, liver cirrhosis, tumor size, tumor encapsulation, AFP and etiologies. Additional subgroup analysis by origin suggested that the prognostic value and clinicopathological significance of cytoplasmic and/or nuclear β-catenin expression was more validated in Asian population. Multivariate analyses of factors showed that cytoplasmic and/or nuclear β-catenin expression, as well as TNM stage, metastasis and tumor size, was an independent risk factors for OS and RFS. Conclusions Cytoplasmic and/or nuclear accumulation of β-catenin, as an independent prognostic factor, significantly associated with poor prognosis and deeper invasion of HCC, and could serve as a valuable prognostic predictor for HCC.

The N-terminal region of p27 inhibits HIF-1α protein translation in ribosomal protein S6-dependent manner by regulating PHLPP-Ras-ERK-p90RSK axis

P27 was identified as a tumor suppressor nearly two decades, being implicated in cell-cycle control, differentiation, senescence, apoptosis and motility. Our present study, for the first time to the best of our knowledge, revealed a potential role of p27 in inhibiting S6-mediated hypoxia-inducible factor-1α (HIF-1α) protein translation, which contributed to the protection from environmental carcinogen (sodium arsenite)-induced cell transformation. Our findings showed that depletion of p27 expression by knockout and knockdown approaches efficiently enhanced S6 phosphorylation in arsenite response via overactivating Ras/Raf/MEK/ERK pathway, which consequently resulted in the stimulation of p90RSK (90 kDa ribosomal S6 kinase), a direct kinase for S6 phosphorylation. Although PI3K/AKT pathway was also involved in S6 activation, blocking AKT and p70S6K activation did not attenuate arsenite-induced S6 activation in p27−/− cells, suggesting p27 specifically targeted Ras/ERK pathway rather than PI3K/AKT pathway for inhibition of S6 activation in response to arsenite exposure. Further functional studies found that p27 had a negative role in cell transformation induced by chronic low-dose arsentie exposure. Mechanistic investigations showed that HIF-1α translation was upregulated in p27-deficient cells in an S6 phosphorylation-dependent manner and functioned as a driving force in arsenite-induced cell transformation. Knockdown of HIF-1α efficiently reversed arsenite-induced cell transformation in p27-depleted cells. Taken together, our findings provided strong evidence showing that by targeting Ras/ERK pathway, p27 provided a negative control over HIF-1α protein synthesis in an S6-dependent manner, and abrogated arsenite-induced cell transformation via downregulation of HIF-1α translation.

ELF3 promotes epithelial–mesenchymal transition by protecting ZEB1 from miR-141-3p-mediated silencing in hepatocellular carcinoma

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.

Phosphorylated ERK is a potential prognostic biomarker for Sorafenib response in hepatocellular carcinoma

Sorafenib, the only approved drug for hepatocellular carcinoma, acts as a remarkable inhibitor of Raf serine‐threonine kinases. However, Sorafenib is expensive, and clinical experience shows that it is not an effective treatment for many patients. Previous study has demonstrated that phosphorylated ERK (pERK) is a key downstream component in the RAF/MEK/ERK signaling pathway. Here, we investigate whether pERK is a useful biomarker for treating HCC with Sorafenib. In vitro cell viability assays showed that the efficacy of Sorafenib was distinctly different according to the level of pERK. Furthermore, in established patient‐derived xenografts from HCC specimens, we found that the growth rate of tumors with high levels of pERK was significantly decreased by Sorafenib treatment. Taken together, pERK is a potential biomarker for the sensitivity to Sorafenib in treating HCC.

Is Laparoscopic Hepatectomy a Safe, Feasible Procedure in Patients with a Previous Upper Abdominal Surgery?

Background:Laparoscopic liver resection has become an accepted treatment for liver tumors or intrahepatic bile duct stones, but its application in patients with previous upper abdominal surgery is controversial. The aim of this study was to evaluate the feasibility and safety of laparoscopic hepatectomy in these patients. Methods:Three hundred and thirty-six patients who underwent laparoscopic hepatectomy at our hospital from March 2012 to June 2015 were enrolled in the retrospective study. They were divided into two groups: Those with previous upper abdominal surgery (PS group, n = 42) and a control group with no previous upper abdominal surgery (NS group, n = 294). Short-term outcomes including operating time, blood loss, hospital stay, morbidity, and mortality were compared among the groups. Results:There was no significant difference in median operative duration between the PS group and the NS group (180 min vs. 160 min, P = 0.869). Median intraoperative blood loss was same between the PS group and the control group (200 ml vs. 200 ml, P = 0.907). The overall complication rate was significantly lower in the NS group than in the PS group (17.0% vs. 31.0%, P = 0.030). Mortality and other short-term outcomes did not differ significantly between groups. Conclusions:Our study showed no significant difference between the PS group and NS group in term of short-term outcomes. Laparoscopic hepatectomy is a feasible and safe procedure for patients with previous upper abdominal surgery.

The ALPPS in the Treatment of Hepatitis B–Related Hepatocellular Carcinoma With Cirrhosis: A Single-Center Study and Literature Review

Background. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) has been reported to be a new treatment strategy for patients with predicted small volumes of future liver remnant (FLR). ALPPS is associated with rapid hypertrophy of FLR but it has a high postoperative mortality and morbidity. Up to now, it is controversial to apply ALPPS in hepatocellular carcinoma, especially for patients with liver cirrhosis. Methods. Between May 2014 and June 2015, consecutive patients who underwent ALPPS with hepatitis B–related hepatocellular carcinoma with cirrhosis carried out in our center were included into the study. Demographic characteristics, surgical outcomes, and pathological results were evaluated. Subsequently, follow-up was still in progress. Results. The median operating time of the first (n = 12) and the second procedures (n = 10) were 285.0 and 212.5 minutes, respectively. The median blood loss were 200 and 800 mL for 2 stages of operations. The severe complication (≥IIIB) rates for the first and the second operations were 25.0% versus 40.0%, respectively. Six patients with too small future live remnant died of postoperative hepatic failure. On a median follow-up of 16 months of the 6 patients discharged, 4 patients were still alive and of 2 were disease-free. Conclusion. 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.

Postoperative adjuvant TACE for patients of hepatocellular carcinoma in AJCC stage I: friend or foe? a propensity score analysis

Background Although the transcatheter arterial chemoembolization (TACE) was demonstrated to be an alternative treatment of hepatocellular carcinoma with favorable oncological effect, the benefit of postoperative adjuvant TACE was still controversial. The aim of this study was to evaluate the effect of postoperative TACE in hepatocellular carcinoma. Results The 1, 3, and 5–year overall and disease–free survival rates were comparable between Surgery+TACE and Surgery groups. In subgroup analysis, tumor size (≥ 5 cm) was detrimental to disease–free survival (p = 0.028) and an inferior tendency of overall survival was presented. Besides, repeated TACE for patients contributed to a poor disease–free survival (p = 0.005). While, postoperative adjuvant TACE improved the overall survival in patients with high preoperative alpha–fetoprotein or positive pathologically (p = 0.039 and p = 0.045). Materials and Methods The data were collected from consecutive patients between January 2010 and September 2014. After propensity score matching, baseline characteristics, overall and disease–free survival were compared between two groups. Subsequently, univariate and subgroup analysis were carried on. Conclusions Our study indicated that single postoperative adjuvant TACE was beneficial for selected patients of stage I with tumor less than 5 cm, or high preoperative alpha–fetoprotein in serum or positive of alpha–fetoprotein pathologically.