Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma

L’Hermitte, Antoine; Pham, Sandrine; Cadoux, Mathilde; Couchy, Gabrielle; Caruso, Stefano; Anson, Marie; Crain-Denoyelle, Anne-Marie; Celton-Morizur, Séverine; Yamagoe, Satoshi; Zucman‐Rossi, Jessica; Desdouets, Chantal; Couty, Jean-Pierre

doi:10.1002/hep.30140

Cited by 40 publications

(38 citation statements)

References 43 publications

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“…Apart from OPN, the role of LECT2, SLC10A1, CYP3A4, and HSD17B13 are also characterized in HCC. LECT2 (Leukocyte cell-derived chemotoxin 2) is originally identified as a chemotactic factor for neutrophils and stimulates the growth of chondrocytes and osteoblasts and acts as a tumor suppressor in HCC by multiple mechanisms, such as inactivation of MET, controlling inflammatory monocytes, and inhibition of VEGF165/VEGFR2-dependent signaling [41][42][43]. Downregulated SLC10A1 is correlated with poor post-surgery survival rate and larger tumor tissue mass in HCC patients and ectopic expression of NTCP significantly suppresses HCC cell proliferation [44].…”

Section: Discussionmentioning

confidence: 99%

Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

et al. 2020

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Background Cancer cells primarily utilize aerobic glycolysis for energy production, a phenomenon known as the Warburg effect. Increased aerobic glycolysis supports cancer cell survival and rapid proliferation and predicts a poor prognosis in cancer patients. Methods Molecular profiles from The Cancer Genome Atlas (TCGA) cohort were used to analyze the prognostic value of glycolysis gene signature in human cancers. Gain- and loss-of-function studies were performed to key drivers implicated in hepatocellular carcinoma (HCC) glycolysis. The molecular mechanisms underlying Osteopontin (OPN)-mediated glycolysis were investigated by real-time qPCR, western blotting, immunohistochemistry, luciferase reporter assay, and xenograft and diethyl-nitrosamine (DEN)-induced HCC mouse models. Results Increased glycolysis predicts adverse clinical outcome in many types of human cancers, especially HCC. Then, we identified a handful of differentially expressed genes related to HCC glycolysis. Gain- and loss-of-function studies showed that OPN promotes, while SPP2, LECT2, SLC10A1, CYP3A4, HSD17B13, and IYD inhibit HCC cell glycolysis as revealed by glucose utilization, lactate production, and extracellular acidification ratio. These glycolysis-related genes exhibited significant tumor-promoting or tumor suppressive effect on HCC cells and these effects were glycolysis-dependent. Mechanistically, OPN enhanced HCC glycolysis by activating the αvβ3-NF-κB signaling. Genetic or pharmacological blockade of OPN-αvβ3 axis suppressed HCC glycolysis in xenograft tumor model and hepatocarcinogenesis induced by DEN. Conclusions Our findings reveal crucial determinants for controlling the Warburg metabolism in HCC cells and provide a new insight into the oncogenic roles of OPN in HCC.

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Section: Discussionmentioning

confidence: 99%

Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

et al. 2020

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“…Shom Goel et al recently found that CDK4/6 inhibitors could promote tumor immunogenicity and may have synergistic effects with immunotherapy . It was reported that the downregulation of LECT2 fostered the accumulation of inflammatory monocytes, which harbor immunosuppressive properties, and promoted the progression of hepatocellular carcinoma . PD1 is mainly expressed on effector T cells in tumor tissues in HCC.…”

Section: Discussionmentioning

confidence: 99%

A signature of 33 immune‐related gene pairs predicts clinical outcome in hepatocellular carcinoma

Sun

Zhang

et al. 2020

Cancer Medicine

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Objective: Hepatocellular carcinoma (HCC) has become the second most common tumor type that contributes to cancer-related death worldwide. The study aimed to establish a robust immune-related gene pair (IRGP) signature for predicting the prognosis of HCC patients. Methods: Two RNA-seq datasets (The Cancer Genome Atlas Program and International Cancer Genome Consortium) and one microarray dataset (GSE14520) were included in this study. We used a series of immune-related genes from the ImmPort database to construct gene pairs. Lasso penalized Cox proportional hazards regression was employed to develop the best prognostic signature. We assigned patients into two groups with low immune risk and high immune risk. Then, the prognostic ability of the signature was evaluated by a log-rank test and a Cox proportional hazards regression model. Results: After 1000 iterations, the 33-immune gene pair model obtained the highest frequency. As a result, we chose the 33 immune gene pairs to establish the immunerelated prognostic signature. As we expected, the immune-related signature accurately predicted the prognosis of HCC patients, and high-risk groups showed poor prognosis in the training datasets and testing datasets as well as in the validation datasets. Furthermore, the immune-related gene pair (IRGP) signature also showed higher predictive accuracy than three existing prognostic signatures. Conclusion: Our prognostic signature, which reflects the link between the immune microenvironment and HCC patient outcome, is promising for prognosis prediction in HCC.

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“…As an aggressive malignancy, HCC is characterized by high recurrence rate and mortality. With accumulating deep sequencing results, substantial amounts of ncRNAs are reported to be dysregulated in HCC (Liu et al, 2019; L'Hermitte et al, 2019). However, few studies have explored the role of circRNAs in HCC.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA PVT1/miR-203/HOXD3 pathway promotes the progression of human hepatocellular carcinoma

et al. 2019

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Accumulating evidence suggests that circular RNAs (circRNAs) play important roles in various physiological and pathological processes. In the present study, we explored the role of circRNA PVT1 in hepatocellular carcinoma (HCC). qRT-PCR was performed to detect the relative expression of circPVT1 in HCC tissues and cell lines. The oncogenic roles of circPVT1 in HCC were evaluated by cell counting kit-8 (CCK-8) assay, ethynyl deoxyuridine (EdU) incorporation assays, transwell assays, flow cytometry and in vivo xenograft growth. Furthermore, bioinformatics, luciferase reporter assays and rescue experiments were conducted to determine the underlying mechanism of circPVT1 in HCC. Enhanced circPVT1 expression was detected in HCC tissues, which was closely associated with poor prognosis of patients with HCC. Knockdown of circPVT1 decreased the proliferation and migration ability of HCC cell lines in vitro. Conversely, upregulation of circPVT1 improved the growth and migration in HCC cells. Mechanistically, we found that circPVT1 could bind directly to miR-203 and contributed to the initiation and progression of HCC by regulating miR-203/homebox D3 (HOXD3) pathway. In conclusion, our study reveals that circPVT1 participates in the progression of HCC through the miR-203/homeobox D3 (HOXD3) pathway and might represent a potential therapeutic target for HCC treatment.

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Lect2 Controls Inflammatory Monocytes to Constrain the Growth and Progression of Hepatocellular Carcinoma

Abstract: our findings have demonstrated that LECT2 is an key player of liver tumorigenesis as its absence reshapes the TME and the tumor phenotype revealing LECT2 as a promising immunotherapeutic option for HCC. This article is protected by copyright. All rights reserved.

Cited by 40 publications

References 43 publications

Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

Integrated analysis reveals critical glycolytic regulators in hepatocellular carcinoma

A signature of 33 immune‐related gene pairs predicts clinical outcome in hepatocellular carcinoma

Circular RNA PVT1/miR-203/HOXD3 pathway promotes the progression of human hepatocellular carcinoma

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