Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells

Son, Yeonghoon; Shin, Na‐Rae; Kim, Sung Hoon; Park, Su-Cheol; Lee, Hae-Jun

doi:10.3390/ijms22105330

Cited by 20 publications

(13 citation statements)

References 35 publications

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“…A previous study has shown that the suppression of FGL1 inhibits the expression of caspase 3 and PARP1, thereby enhancing the inhibitory and apoptosis-inducing activities of gefitinib in the non-small cell lung cancer (NSCLC) cell line PC9/GR [27]. Similarly, Son et al [28] reported that sorafenib-induced anti-tumor effects were enhanced by knocking down FGL1. Interestingly, high expression levels of FGL1 are related to high densities of LAG-3 + cells, confirming that FGL1 is a highaffinity ligand for LAG-3 [29].…”

Section: Discussionmentioning

confidence: 93%

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma

et al. 2022

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Background Fibrinogen-like-protein 1 (FGL1), a member of the fibrinogen-related protein (FREP) family, is a major ligand of the immune inhibitory receptor lymphocyte-activation gene 3 (LAG-3). While FGL1 is strongly implicated in the development and prognosis of a variety of diseases, its role in hepatocellular carcinoma (HCC) is still disputed. Therefore, the role of FGL1 expression in the progression and prognosis of HCC was investigated. Methods and results In the present study, bioinformatics analysis was first used to probe the expression profile of FGL1 in multiple malignant tumor tissues and paired normal tissues, and to explore the possible relationship between FGL1 and prognosis of HCC patients. Thereafter, the expression levels of FGL1 were determined and compared in human HCC cell lines, HCC tissues, peri-tumor tissues and normal liver tissues by western blot analysis. Furthermore, tissue microarrays were used to detect the expression of FGL1 through immunohistochemical staining and to verify whether the FGL1 expression level was associated with clinicopathological features and the prognosis of HCC patients. The results showed that FGL1 was downregulated significantly in most of the HCC cells lines and HCC tissues, corresponding to the results of the bioinformatics and western blot analyses. FGL1 expression level in HCC was found to be correlated to Edmondson grade and metastasis of the HCC. Additionally, high FGL1 expression was associated with better overall survival in HCC patients, suggesting that FGL1 could function as a tumor suppressor. Conclusions The expression level of FGL1 can be correlated with the progression and prognosis of HCC, suggesting its potential as a prognostic biomarker.

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Section: Discussionmentioning

confidence: 93%

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma

et al. 2022

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“…Furthermore, the colony forming function and IC50 values were two- to three-fold higher in the low FGL1 expression group compared to those of the high FGL1 expression group. The specific mechanisms may involve the high expression of FGL1, which may influence MAPK and autophagy-related signaling, verified by FGL1 silencing ( 97 ). Anti-PD1/CTLA-4 therapy is an effective immunotherapy for the highly metastatic uveal melanoma.…”

Section: Clinical Application Of Lag3/fglmentioning

confidence: 99%

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

et al. 2022

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LAG3 is the most promising immune checkpoint next to PD-1 and CTLA-4. High LAG3 and FGL1 expression boosts tumor growth by inhibiting the immune microenvironment. This review comprises four sections presenting the structure/expression, interaction, biological effects, and clinical application of LAG3/FGL1. D1 and D2 of LAG3 and FD of FGL1 are the LAG3-FGL1 interaction domains. LAG3 accumulates on the surface of lymphocytes in various tumors, but is also found in the cytoplasm in non-small cell lung cancer (NSCLC) cells. FGL1 is found in the cytoplasm in NSCLC cells and on the surface of breast cancer cells. The LAG3-FGL1 interaction mechanism remains unclear, and the intracellular signals require elucidation. LAG3/FGL1 activity is associated with immune cell infiltration, proliferation, and secretion. Cytokine production is enhanced when LAG3/FGL1 are co-expressed with PD-1. IMP321 and relatlimab are promising monoclonal antibodies targeting LAG3 in melanoma. The clinical use of anti-FGL1 antibodies has not been reported. Finally, high FGL1 and LAG3 expression induces EGFR-TKI and gefitinib resistance, and anti-PD-1 therapy resistance, respectively. We present a comprehensive overview of the role of LAG3/FGL1 in cancer, suggesting novel anti-tumor therapy strategies.

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“… 29 The expression of FGL1 not only affects the regeneration of hepatocytes, but also regulates the growth and proliferation of tumor cells. 30 , 31 The research shows that FGL1 is the main inhibitory ligand of lymphocyte activation gene 3 (LAG-3), which can inhibit antigen-specific T cell responses through the interaction of FGL1/LAG-3. 32 Blockade of the inhibiting signal of FGL1/LAG-3 by knockout of FGL1 or function-blocking monoclonal antibody (mAb) can enhance T cell immunity in the tumor microenvironment and inhibit tumor growth.…”

Section: Introductionmentioning

confidence: 99%

Dual-targeting vaccine of FGL1/CAIX exhibits potent anti-tumor activity by activating DC-mediated multi-functional CD8 T cell immunity

Chai

Qin

Shi

et al. 2022

Molecular Therapy - Oncolytics

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Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c + DCs and CD11c + CD11b + DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8 + T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8 + T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8 + T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8 + T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8 + T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment.

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Fibrinogen-Like Protein 1 Modulates Sorafenib Resistance in Human Hepatocellular Carcinoma Cells

Cited by 20 publications

References 35 publications

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma

The correlation of fibrinogen-like protein-1 expression with the progression and prognosis of hepatocellular carcinoma

Immune Checkpoint LAG3 and Its Ligand FGL1 in Cancer

Dual-targeting vaccine of FGL1/CAIX exhibits potent anti-tumor activity by activating DC-mediated multi-functional CD8 T cell immunity

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