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

Springer Science and Business Media LLC - Tập 49 - Trang 7911-7919 - 2022
Nanni Hua1,2, Anxian Chen3, Chen Yang4, Hui Dong5, Xianglei He6, Guoqing Ru6, Xiangmin Tong2, Feifei Zhou7, Shibing Wang2
1The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China;
2Cancer Center, Molecular Diagnosis Laboratory, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, People’s Republic of China
3School of Public Health (Shenzhen), Shenzhen Campus of Sun Yat-sen University, Shenzhen, China
4Department of Ultrasound, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, China
5Department of Stomatology, Bengbu Medical College, Bengbu, China
6Departments of Pathology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China
7Departments of TCM Gynecology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, China

Tóm tắt

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. 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. The expression level of FGL1 can be correlated with the progression and prognosis of HCC, suggesting its potential as a prognostic biomarker.

Tài liệu tham khảo

Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249. https://doi.org/10.3322/caac.21660 Allemani C, Matsuda T, Di Carlo V et al (2018) Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 391(10125):1023–1075. https://doi.org/10.1016/S0140-6736(17)33326-3 Zhang G, Ha SA, Kim HK et al (2012) Combined analysis of AFP and HCCR-1 as an useful serological marker for small hepatocellular carcinoma: a prospective cohort study. Dis Markers 32(4):265–271. https://doi.org/10.3233/DMA-2011-0878 De Stefano F, Chacon E, Turcios L et al (2018) Novel biomarkers in hepatocellular carcinoma. Dig Liver Dis 50(11):1115–1123. https://doi.org/10.1016/j.dld.2018.08.019 Demchev V, Malana G, Vangala D et al (2013) Targeted deletion of fibrinogen like protein 1 reveals a novel role in energy substrate utilization. PLoS ONE 8(3):e58084. https://doi.org/10.1371/journal.pone.0058084 Yu J, Li J, Shen J et al (2021) The role of fibrinogen-like proteins in cancer. Int J Biol Sci 17(4):1079–1087. https://doi.org/10.7150/ijbs.56748 Yamamoto T, Gotoh M, Sasaki H et al (1993) Molecular cloning and initial characterization of a novel fibrinogen-related gene, HFREP-1. Biochem Biophys Res Commun 193(2):681–687. https://doi.org/10.1006/bbrc.1993.1678 Rijken DC, Dirkx SPG, Luider TM et al (2006) Hepatocyte-derived fibrinogen-related protein-1 is associated with the fibrin matrix of a plasma clot. Biochem Biophys Res Commun 350(1):191–194. https://doi.org/10.1016/j.bbrc.2006.09.018 Wu HT, Chen SC, Fan KC et al (2020) Targeting fibrinogen-like protein 1 is a novel therapeutic strategy to combat obesity. FASEB J 34(2):2958–2967. https://doi.org/10.1096/fj.201901925R Liu Z, Ukomadu C (2008) Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant. Biochem Biophys Res Commun 365(4):729–734. https://doi.org/10.1016/j.bbrc.2007.11.069 Gao M, Zhan Y-Q, Yu M et al (2014) Hepassocin activates the EGFR/ERK cascade and induces proliferation of L02 cells through the Src-dependent pathway. Cell Signal 26(10):2161–2166. https://doi.org/10.1016/j.cellsig.2014.04.013 Wu H-T, Lu F-H, Ou H-Y et al (2013) The role of hepassocin in the development of non-alcoholic fatty liver disease. J Hepatol 59(5):1065–1072. https://doi.org/10.1016/j.jhep.2013.06.004 Hara H, Yoshimura H, Uchida S et al (2001) Molecular cloning and functional expression analysis of a cDNA for human hepassocin, a liver-specific protein with hepatocyte mitogenic activity. Biochim Biophys Acta 1520(1):45–53. https://doi.org/10.1016/s0167-4781(01)00249-4 Han NK, Jung MG, Jeong YJ et al (2019) Plasma fibrinogen-like 1 as a potential biomarker for radiation-induced liver injury. Cells. https://doi.org/10.3390/cells8091042 Hara H, Uchida S, Yoshimura H et al (2000) Isolation and characterization of a novel liver-specific gene, hepassocin, upregulated during liver regeneration. Biochim Biophys Acta 1492(1):31–44. https://doi.org/10.1016/s0167-4781(00)00056-7 Zhang Y, Qiao HX, Zhou YT et al (2018) Fibrinogen-like-protein 1 promotes the invasion and metastasis of gastric cancer and is associated with poor prognosis. Mol Med Rep 18(2):1465–1472. https://doi.org/10.3892/mmr.2018.9097 Nayeb-Hashemi H, Desai A, Demchev V et al (2015) Targeted disruption of fibrinogen like protein-1 accelerates hepatocellular carcinoma development. Biochem Biophys Res Commun 465(2):167–173. https://doi.org/10.1016/j.bbrc.2015.07.078 Wang J, Sanmamed MF, Datar I et al (2019) Fibrinogen-like protein 1 is a major immune inhibitory ligand of LAG-3. Cell 176:334-347.e12. https://doi.org/10.1016/j.cell.2018.11.010 Luo P, Wu S, Yu Y et al (2020) Current status and perspective biomarkers in AFP negative HCC: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Pathol Oncol Res 26(2):599–603. https://doi.org/10.1007/s12253-019-00585-5 Tsuchiya N, Sawada Y, Endo I et al (2015) Biomarkers for the early diagnosis of hepatocellular carcinoma. World J Gastroenterol 21(37):10573–10583. https://doi.org/10.3748/wjg.v21.i37.10573 Li CY, Cao CZ, Xu WX et al (2010) Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure. Gut 59(6):817–826. https://doi.org/10.1136/gut.2008.171124 Yan J, Ying H, Gu F et al (2002) Cloning and characterization of a mouse liver-specific gene mfrep-1, up-regulated in liver regeneration. Cell Res 12:353–361. https://doi.org/10.1038/sj.cr.7290137 Yan J, Yu Y, Wang N et al (2004) LFIRE-1/HFREP-1, a liver-specific gene, is frequently downregulated and has growth suppressor activity in hepatocellular carcinoma. Oncogene 23(10):1939–1949. https://doi.org/10.1038/sj.onc.1207306 Cao MM, Xu WX, Li CY et al (2011) Hepassocin regulates cell proliferation of the human hepatic cells L02 and hepatocarcinoma cells through different mechanisms. J Cell Biochem 112(10):2882–2890. https://doi.org/10.1002/jcb.23202 Yu HT, Yu M, Li CY et al (2009) Specific expression and regulation of hepassocin in the liver and down-regulation of the correlation of HNF1alpha with decreased levels of hepassocin in human hepatocellular carcinoma. J Biol Chem 284(20):13335–13347. https://doi.org/10.1074/jbc.M806393200 Bie F, Wang G, Qu X et al (2019) Loss of FGL1 induces epithelial-mesenchymal transition and angiogenesis in LKB1 mutant lung adenocarcinoma. Int J Oncol 55(3):697–707. https://doi.org/10.3892/ijo.2019.4838 Sun C, Gao W, Liu J et al (2020) FGL1 regulates acquired resistance to Gefitinib by inhibiting apoptosis in non-small cell lung cancer. Respir Res 21(1):210. https://doi.org/10.1186/s12931-020-01477-y Son Y, Shin NR, Kim SH et al (2021) Fibrinogen-like protein 1 modulates sorafenib resistance in human hepatocellular carcinoma cells. Int J Mol Sci. https://doi.org/10.3390/ijms22105330 Guo M, Yuan F, Qi F et al (2020) Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8T cells in hepatocellular carcinoma using multiplex quantitative analysis. J Transl Med 18(1):306. https://doi.org/10.1186/s12967-020-02469-8 Zhang WT, Liu TT, Wu M et al (2021) Development of a nanobody-based immunoassay for the sensitive detection of fibrinogen-like protein 1. Acta Pharmacol Sin 42(11):1921–1929. https://doi.org/10.1038/s41401-020-00574-4 Wang J, Wei W, Tang Q et al (2020) Oxysophocarpine suppresses hepatocellular carcinoma growth and sensitizes the therapeutic blockade of anti-Lag-3 via reducing FGL1 expression. Cancer Med 9(19):7125–7136. https://doi.org/10.1002/cam4.3151