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Jin Lei,1,* Sibo Yang,1,* Bowen Chen,2,* Linzhi Zhang,3 Tao Yan,3 Gangqi Yang,1 Yue Chen,1 Yinyin Li,3 Yinying Lu,1,3,4 Shi Zuo1,5 1School of Clinical Medicine, Guizhou Medical University, Guiyang, People’s Republic of China; 2 302 Clinical Medical School, Peking University, Beijing, People’s Republic of China; 3Comprehensive Liver Cancer Center, the 5th Medical Center of the PLA General Hospital, Beijing, People’s Republic of China; 4Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua, Beijing, People’s Republic of China; 5Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yinying Lu; Shi Zuo, Tel +86 13301256799 ; +86 13908516978, Email luyinying1973@163.com; drzuoshi@gmc.edu.cnBackground: Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC).Methods: The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated.Results: Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3– 4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238).Conclusion: The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.Keywords: hepatitis C virus, hepatitis C virus reactivation, hepatocellular carcinoma, tyrosine kinase inhibitor, programmed death-1 inhibitor

The chemokine, C-X-C motif chemokine ligand 12 (CXCL12) and its G-protein-coupled receptor (GPCR) and C-X-C chemokine receptor type 4 (CXCR4), are closely associated with promoting hepatocellular carcinoma (HCC) chemotaxis and metastasis. The binding of CXCL12 and CXCR4 depends on the heterotrimeric Gi proteins to regulate actin polymerisation and mobility in HCC. Although the role of GPCR/Gi signalling in carcinogenesis migration has been intensively studied, the detailed mechanism remains largely unknown. In this study, a small interfering RNA technique was used to knock down the Nucleophosmin 1 (NPM1) gene expression. Through the chemotaxis and invasion assays, wound healing, proliferation, filamentous-actin, immunofluorescence, immunohistochemical assays, and co-immunoprecipitation assays, we investigated the specific biological role and underlying mechanisms of the NPM1 in HCC. Additionally, dimethyl fumarate (DMF), a fumaric acid ester, was used to inhibit the HCC cell chemokines and metastasis by regulating ELMO1 and NPM1. Therefore, this study reported that NPM1 gene expression was upregulated in the HCC tissues and cell lines. The NPM1 knockdown significantly inhibited the proliferation, migration, and chemotaxis of the HepG2 cells in vitro. Further mechanistic studies suggested that the NPM1 interacts with ELMO1 and the CXCL12/CXCR4 pathway activates NPM1-dependent regulation of the ELMO1 localisation. Furthermore, the DMF significantly inhibited tumour metastasis induced by the NPM1/ELMO1 signalling pathway, as observed in in vitro cell functional experiments. These data suggested that as a potentially novel therapeutic approach, the simultaneous targeting of NPM1 and ELMO1 could effectively be used to treat HCC.