The overexpression of hypoxia-inducible factor 1α (HIF-1α) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, ...has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1α expression and activation in HCC cells and xenografts.
HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1α activity, de novo protein synthesis, and VEGF secretions were determined using assay kits.
Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that such reduction of HIF-1α was associated with the inhibition of HIF-1α protein synthesis rather than the promotion of HIF-1α protein degradation or the reduction of HIF-1α mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1α and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts.
Sorafenib-mediated inhibition of HIF-1α synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1α and VEGF protein expression.
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men, but the molecular mechanism remains obscure. Here, we show that an androgen receptor (AR)-driven oncogene, cell ...cycle-related kinase (CCRK), collaborates with obesity-induced pro-inflammatory signaling to promote non-alcoholic steatohepatitis (NASH)-related hepatocarcinogenesis. Lentivirus-mediated Ccrk ablation in liver of male mice fed with high-fat high-carbohydrate diet abrogates not only obesity-associated lipid accumulation, glucose intolerance and insulin resistance, but also HCC development. Mechanistically, CCRK fuels a feedforward loop by inducing STAT3-AR promoter co-occupancy and transcriptional up-regulation, which in turn activates mTORC1/4E-BP1/S6K/SREBP1 cascades via GSK3β phosphorylation. Moreover, hepatic CCRK induction in transgenic mice stimulates mTORC1-dependent G
csf expression to enhance polymorphonuclear myeloid-derived suppressor cell recruitment and tumorigenicity. Finally, the STAT3-AR-CCRK-mTORC1 pathway components are concordantly over-expressed in human NASH-associated HCCs. These findings unveil the dual roles of an inflammatory-CCRK circuitry in driving metabolic and immunosuppressive reprogramming through mTORC1 activation, thereby establishing a pro-tumorigenic microenvironment for HCC development.
Purpose: This study aims to profile the expressions of 156 microRNAs (miRNA) in hepatocellular carcinoma (HCC) and to characterize
the functions of miR-222, the most significantly upregulated ...candidate identified.
Experimental Design: miRNA expression profile in HCC tumors, matching adjacent cirrhotic livers, and cell lines was conducted using quantitative
PCR. Common miR-222 upregulations were further validated in a larger cohort of tumors. The functional effects of miR-222 inhibition
on HCC cell lines were examined. The downstream modulated pathways and target of miR-222 were investigated by coupling gene
expression profiling and pathway analysis, and by in silico prediction, respectively. Luciferase reporter assay was done to confirm target interaction.
Results: We identified a 40-miRNA signature that could discriminate tumors from adjacent cirrhotic liver tissue, and further corroborated
common miR-222 overexpression in tumors relative to its premalignant counterpart (55.3%; P < 0.0001). Increased miR-222 expression correlated significantly with advanced stage HCC and with the shorter disease-free
survival of patients ( P ≤ 0.01). Inhibition of miR-222 in Hep3B and HKCI-9 significantly retarded cell motility ( P < 0.05). Further investigations suggested that AKT signaling was the major pathway influenced by miR-222. A consistent reduction
of AKT phosphorylation in Hep3B and HKCI-9 was shown following miR-222 suppression. The protein phosphatase 2A subunit B (PPP2R2A)
was predicted as a putative miR-222 target in silico . We found that miR-222 inhibition could augment the tumor protein level and restore luciferase activity in reporter construct
containing the PPP2R2A 3′ untranslated region ( P = 0.0066).
Conclusions: Our study showed that miR-222 overexpression is common in HCC and could confer metastatic potentials in HCC cells, possibly
through activating AKT signaling. Clin Cancer Res; 16(3); 867–75
Nasopharyngeal carcinoma (NPC) is an aggressive head and neck cancer characterized by Epstein-Barr virus (EBV) infection and dense lymphocyte infiltration. The scarcity of NPC genomic data hinders ...the understanding of NPC biology, disease progression and rational therapy design. Here we performed whole-exome sequencing (WES) on 111 micro-dissected EBV-positive NPCs, with 15 cases subjected to further whole-genome sequencing (WGS), to determine its mutational landscape. We identified enrichment for genomic aberrations of multiple negative regulators of the NF-κB pathway, including CYLD, TRAF3, NFKBIA and NLRC5, in a total of 41% of cases. Functional analysis confirmed inactivating CYLD mutations as drivers for NPC cell growth. The EBV oncoprotein latent membrane protein 1 (LMP1) functions to constitutively activate NF-κB signalling, and we observed mutual exclusivity among tumours with somatic NF-κB pathway aberrations and LMP1-overexpression, suggesting that NF-κB activation is selected for by both somatic and viral events during NPC pathogenesis.
The poor clinical outcome of hepatocellular carcinoma (HCC) patients is ascribed to the resistance of HCC cells to traditional treatments and tumor recurrence after curative therapies. Cancer stem ...cells (CSCs) have been identified as a small subset of cancer cells which have high capacity for self-renewal, differentiation and tumorigenesis. Recent advances in the field of liver CSCs (LCSCs) have enabled the identification of CSC surface markers and the isolation of CSC subpopulations from HCC cells. Given their central role in cancer initiation, metastasis, recurrence and therapeutic resistance, LCSCs constitute a therapeutic opportunity to achieve cure and prevent relapse of HCC. Thus, it is necessary to develop therapeutic strategies to selectively and efficiently target LCSCs. Small molecular inhibitors targeting the core stemness signaling pathways have been actively pursued and evaluated in preclinical and clinical studies. Other alternative therapeutic strategies include targeting LCSC surface markers, interrupting the CSC microenvironment, and altering the epigenetic state. In this review, we summarize the properties of CSCs in HCC and discuss novel therapeutic strategies that can be used to target LCSCs.
Background
The development of robotic system may help to relieve the difficulties encountered during laparoscopic hepatectomy. A difficulty scoring system (DSS) was developed to assess the difficulty ...of various laparoscopic liver resection procedures. The aim of this study is to explore if the DSS is applicable in robotic hepatectomy and to compare the outcomes of robotic hepatectomy and laparoscopic hepatectomy among different difficulty levels.
Methods
Clinical data from all consecutive patients who underwent robotic and conventional laparoscopic hepatectomy at the Prince of Wales Hospital, Hong Kong, were prospectively collected and reviewed. The difficulty level of operations was graded using the DSS. Perioperative outcomes of robotic and conventional laparoscopic hepatectomy were compared at each difficulty level.
Results
A total of 107 and 94 patients underwent robotic and laparoscopic hepatectomy during the study period, respectively. Among them, 16 and 2 patients were operated for recurrent pyogenic cholangitis, respectively, and were excluded because no mark for tumour location can be assigned. For robotic hepatectomy, a higher DSS was significantly correlated with higher minor complication rate (
p
= 0.001), more intraoperative blood loss (
p
= 0.002), longer operation time (
p
< 0.001) and longer post-operative hospital stay (
p
< 0.001). The mean DSS scores of robotic and laparoscopic hepatectomy were 4.5 and 3.6, respectively. (
p
= 0.004). For cases with low (DSS 1–3) and intermediate (DSS 4–6) difficulty level, there was no significant difference in operative blood loss, operation time and overall complications rate. Only 2 cases (2.2%) with high difficulty level were operated with laparoscopic approach while 20% of patients operated with robotic approach had DSS > 6.
Conclusions
DSS significantly correlated with surgical outcomes in patient who underwent robotic hepatectomy. Perioperative outcomes following robotic and conventional laparoscopic hepatectomy were similar in cases with low and intermediate difficulty. However, robotic system allowed minimally invasive approach in cases with higher difficulty level.
Obesity is a major risk factor for cancers including hepatocellular carcinoma (HCC) that develops from a background of non-alcoholic fatty liver disease (NAFLD). Hypercholesterolemia is a common ...comorbidity of obesity. Although cholesterol biosynthesis mainly occurs in the liver, its role in HCC development of obese people remains obscure. Using high-fat high-carbohydrate diet-associated orthotopic and spontaneous NAFLD-HCC mouse models, we found that hepatic cholesterol accumulation in obesity selectively suppressed natural killer T (NKT) cell-mediated antitumor immunosurveillance. Transcriptome analysis of human liver revealed aberrant cholesterol metabolism and NKT cell dysfunction in NAFLD patients. Notably, cholesterol-lowering rosuvastatin restored NKT expansion and cytotoxicity to prevent obesogenic diet-promoted HCC development. Moreover, suppression of hepatic cholesterol biosynthesis by a mammalian target of rapamycin (mTOR) inhibitor vistusertib preceded tumor regression, which was abolished by NKT inactivation but not CD8
T cell depletion. Mechanistically, sterol regulatory element-binding protein 2 (SREBP2)-driven excessive cholesterol production from hepatocytes induced lipid peroxide accumulation and deficient cytotoxicity in NKT cells, which were supported by findings in people with obesity, NAFLD and NAFLD-HCC. This study highlights mTORC1/SREBP2/cholesterol-mediated NKT dysfunction in the tumor-promoting NAFLD liver microenvironment, providing intervention strategies that invigorating NKT cells to control HCC in the obesity epidemic.
Background
Laparoscopic liver resection (LLR) of high difficulty score is technically challenging. There is a lack of clinical evidence to support its applicability in terms of the long-term survival ...benefits. This study aims to compare clinical outcomes between LLR and the open liver resection of high difficulty score for hepatocellular carcinoma (HCC).
Materials and Methods
From 2010 to 2020, using Iwate criteria, 424 patients underwent liver resection of high difficulty score by the laparoscopic (
n
= 65) or open (
n
= 359) approach. Propensity score (PS) matching was performed between the two groups. Short-term and long-term outcomes were compared between PS-matched groups. Univariate and multivariate analyses were performed to identify prognostic factors affecting survival.
Results
The laparoscopic group had significantly fewer severe complications (3% vs. 10.8%), and shorter median hospital stays (6 days vs. 8 days) than the open group. Meanwhile, the long-term oncological outcomes were comparable between the two groups, in terms of the tumor recurrence rate (40% vs. 46.1%), the 5-year overall survival rate (75.4% vs. 76.2%), and the 5-year recurrence-free survival rate (50.3% vs. 53.5%). The high preoperative serum alpha-fetoprotein level, multiple tumors, and severe postoperative complications were the independent poor prognostic factors associated with worse overall survival. The surgical approach (Laparoscopic vs. Open) did not influence the survival.
Conclusion
LLR of high difficulty score for selected patients with HCC has better short-term outcomes than the open approach. More importantly, it can achieve similar long-term survival outcomes as the open approach.
Risk‐adjusted control charts have been widely used in monitoring surgical quality in detecting risks of surgical performance. Most of the previous approaches focus on shifts in the location parameter ...as well as the existence of the scale parameter, which cannot get the full measure of the scale parameter under different levels. Ignoring the magnitude of the scale parameter, the monitoring methods cannot detect different variations of surgical mortality that is measured by scale parameter and required to reflect surgical quality improvement. The method of detecting variations in surgical quality is of interest in surgical quality improvement. This paper uses a new weighted h‐likelihood method to obtain a weighted score test for the surgical risks from the logistic model. Then an exponentially weighted moving average chart can be constructed to monitor the changes in the variance of risks, which could be of interest in practical surgical monitoring programs. Simulation results indicate that the proposed approach performs more efficiently than existing methods under various magnitudes of shifts in scale parameters on top of different pre‐set threshold stability. In addition, the application of the proposed method to real surgical data from the Surgical Outcome Monitoring and Improvement Program in Hong Kong shows the improvement and deterioration in a hospital's outcomes.
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