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The mammalian target of rapamycin (mTOR) pathway is frequently deregulated and has critical roles in cancer progression. mTOR inhibitor has been widely used in several kinds of cancers and is strongly recommended in patients with hepatocellular carcinoma (HCC) after liver transplantation (LT). However, the poor response to mTOR inhibitors due to resistance remains a challenge. Hypoxia‐associated resistance limits the therapeutic efficacy of targeted drugs. The present study established models of HCC clinical samples and cell lines resistance to mTOR inhibitor sirolimus and screened out E2F7 as a candidate gene induced by hypoxia and promoting sirolimus resistance. E2F7 suppressed mTOR complex 1 via directly binding to the promoter of the TSC1 gene and stabilizes hypoxia‐inducible factor‐1α activating its downstream genes, which are responsible for E2F7‐dependent mTOR inhibitor resistance. Clinically, low E2F7 expression could be an effective biomarker for recommending patients with HCC for anti‐mTOR–based therapies after LT. Targeting E2F7 synergistically inhibited HCC growth with sirolimus in vivo. E2F7 is a promising target to reverse mTOR inhibition resistance. Collectively, our study points to a role for E2F7 in promoting mTOR inhibitor resistance in HCC and emphasizes its potential clinical significance in patients with HCC after LT.

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Background: Chloride intracellular channel 1 (CLIC1) is upregulated in hepatocellular carcinoma (HCC). The present study aimed to investigate the role of CLIC1 in HCC angiogenesis. Materials and Methods: Immunohistochemistry (IHC) was used to test the expression of CLIC1 and CD34 in 67 pairs of HCC and paracarcinoma tissues. The prognosis data of the patients were used to analyze the clinical relevance of CLIC1. We built a coculture system of HCC cells and endothelial cells to explore the migration of endothelial cells. Conditioned media (CMs) from HCC cells was then collected to assess endothelial cell migration. Experiments were then conducted to confirm the relationship between CLIC1 and angiogenesis in a subcutaneous tumor model. Results: CLIC1 expression was higher in HCC tumor tissues than in paracarcinoma tissues. Patients with increased CLIC1 expression showed a higher microvascular density (MVD; P = .013). Kaplan-Meier curves indicated that patients with lower expression of CLIC1 had better overall survival ( P < .001) and recurrence-free survival ( P = .046). Vascular endothelial growth factor A (VEGFA) in CMs from CLIC1-knockdown cells was lower than in the control group, while VEGFA in CMs from CLIC1 overexpression cells was higher than in the control group. CMs from CLIC1 overexpression cell lines promote the in vitro migration of EA.hy926 cells. Meanwhile, adding Bevacizumab to CMs from CLIC1 overexpression cells significantly inhibited this migration. The growth of xenograft tumors derived from CLIC1-knockdown Huh7 cells was restrained compared with the control group ( P < .001). IHC staining showed MVD was higher in tumors with CLIC1 overexpression. Conclusion: CLIC1 is a promising biomarker for predicting the prognosis of HCC patients, and expression of CLIC1 correlates with angiogenesis in HCC through regulating VEGFA

The ongoing trends of patient-derived xenograft models in oncology 1 MAIN TEXT Patient-derived xenograft (PDX) models have garnered increasing attention since the last decade. These models are typically characterized by the implantation of fresh patient-derived tumor tissues into immunodeficient mice. PDX models are well recognized in academic laboratories, pharmaceutical institutions, and specialized commercial organizations as having the ability to recapitulate genomics, transcriptomics, proteomics, and metabolomics of the parental tumor tissue [1,2]. Recently, these models have been successfully used in preclinical studies to identify potential biomarkers for drug response and resistance, and to measure tumor evolution in response to treatment [3,4]. Favorable outcomes demonstrated using PDX models could be used as ideal models for preclinical research and clinical translation studies. At present, the concept of co-clinical trial, the simultaneous use of the so-called Avatar models, has attracted growing attention and has been expanded to include PDX models. These Avatar models are generated from patients enrolled in clinical trials and are simultaneously treated with the same anticancer therapies as the patients [5]. Several retrospective studies have shown that responses of PDX models toward certain agents were strongly correlated to the clinical response seen in the patients [6]. Moreover, Avatar models have been involved in 15 clinical trials covering different tumor settings, including prostate cancer, breast cancer, lung cancer, colorectal cancer, sarcoma, head and neck carcinoma, ovarian cancer, and pancreatic cancer (https://ClinicalTrials.gov). Some prospective studies were also performed using PDX models to guide clinical treatment decisions in a small number of patients and demonstrated prolonged survival [7,8]. Stebbing's et al. [8] showed that 20.1% (6/29) of their investigated patients with advanced sarcoma obtained direct clinical benefits from PDX-guided therapy. Bousquet et al. [9] suggested that Abbreviations: CNAs, copy number alterations; PDX, patient-derived xenograft; PDX-MI, PDX model minimal information standard This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Importance: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in patients who undergo liver transplantation (LT). Whereas there is huge data on NAFLD, little is known about NAFLD in LT.Objective: In this review, we aim to explore extrahepatic organs and their potential mechanisms in the development of NAFLD in LT patients and discuss current limitations in preclinical and clinical scenarios with suggestions for future study.Evidence Review: The following keywords, such as NAFLD, NASH, liver transplant, therapy, pathogenesis and biomarkers, were set for literature retrieval. The articles which were published articles in English till 25th June 2020 were included, and there is no limit for the study design type.Findings: Following LT, there are significant shifts in the microbiota and farnesoid X receptor may be a potential therapeutic target for NAFLD in LT settings. The roles of probiotics and diet on NALFD remain inconclusive in LT background. Nevertheless, the adipokines and cytokines disorder and local insulin resistance of adipose tissue may contribute to NAFLD process. Bariatric surgeries are promising in controlling de novo and recurrent NAFLD with significant reduction in abdominal adipose tissue, despite the optimal timing is inconclusive in LT cases. Furthermore, circumstantial evidence indicates that miRNA-33a may function as a mediator bridging sarcopenia and NAFLD of post-LT. β-Hydroxy-β-Methyl-Butyrate treatment could improve muscle status in graft recipients and shows protective potential for NAFLD in LT settings.Conclusions and Relevance: Gut, adipose tissue and muscle are intricately intertwined in promoting NAFLD in LT cases. Further animal studies are needed to deepen our understanding of mechanisms in multi-organ crosstalk. High quality clinical trials are warrant for making guidelines and developing management strategies on NAFLD after LT.