Abstract
Background: Hepatocellular carcinoma (HCC) is the most common liver malignancy where tumorigenesis and metastasis are believed to be tied to the hallmarks of hypoxia and tumor microenvironment (TME).
Methods: In this study, to investigate the relationships among hypoxia, TME, and HCC prognosis, we collected two independent datasets from a public database (TCGA-LIHC for identification, GSE14520 for validation) and identified the hypoxia-related differentially expressed genes (DEGs) from the TCGA data, and the univariable Cox regression and lasso regression analyses were performed to construct the prognosis model. An HCC prognosis model with 4 hypoxiarelated DEGs ("NDRG1", "ENO1", "SERPINE1", "ANXA2") was constructed, and high- and low-risk groups of HCC were established by the median of the model risk score.
Results: The survival analysis revealed significant differences between the two groups in both datasets, with the results of the AUC of the ROC curve of 1, 3, and 5 years in two datasets indicating the robustness of the prognosis model. Meanwhile, for the TCGA-LIHC data, the immune characteristics between the two groups revealed that the low-risk group presented higher levels of activated NK cells, monocytes, and M2 macrophages, and 7 immune checkpoint genes were found upregulated in the high-risk group. Additionally, the two groups have no difference in molecular characteristics (tumor mutational burden, TMB). The proportion of recurrence was higher in the high-risk group, and the correlation between the recurrence month and risk score was negative, indicating high-risk correlates with a short recurrence month.
Conclusion: In summary, this study shows the association among hypoxic signals, TME, and HCC prognosis and may help reveal potential regulatory mechanisms between hypoxia, tumorigenesis, and metastasis in HCC. The hypoxia-related model demonstrated the potential to be a predictor and drug target of prognosis.
Graphical Abstract
[1]
Clark, T.; Maximin, S.; Meier, J.; Pokharel, S.; Bhargava, P. Hepatocellular carcinoma: Review of epidemiology, screening, imaging diagnosis, response assessment, and treatment. Curr. Probl. Diagn. Radiol., 2015, 44(6), 479-486.
[http://dx.doi.org/10.1067/j.cpradiol.2015.04.004] [PMID: 25979220]
[http://dx.doi.org/10.1067/j.cpradiol.2015.04.004] [PMID: 25979220]
[2]
Hepatocellular carcinoma. Nat. Rev. Dis. Primers, 2021, 7(1), 7.
[http://dx.doi.org/10.1038/s41572-021-00245-6] [PMID: 33479233]
[http://dx.doi.org/10.1038/s41572-021-00245-6] [PMID: 33479233]
[3]
Wen, X.; Xiao, Y.; Leng, P.; Luo, H. Comprehensive analysis of prognostic value and immune infiltration of atii-associated genes in non-small cell lung cancer. PREPRINT (Version 1) available at
Research Square, 2021.
[http://dx.doi.org/10.21203/rs.21203.rs-1121362/v1121361]
[http://dx.doi.org/10.21203/rs.21203.rs-1121362/v1121361]
[4]
Mo, Z.; Liu, D.; Rong, D.; Zhang, S. Hypoxic characteristic in the immunosuppressive microenvironment of hepatocellular carcinoma. Front. Immunol., 2021, 12, 611058.
[http://dx.doi.org/10.3389/fimmu.2021.611058] [PMID: 33679749]
[http://dx.doi.org/10.3389/fimmu.2021.611058] [PMID: 33679749]
[5]
Couri, T.; Pillai, A. Goals and targets for personalized therapy for HCC. Hepatol. Int., 2019, 13(2), 125-137.
[http://dx.doi.org/10.1007/s12072-018-9919-1] [PMID: 30600478]
[http://dx.doi.org/10.1007/s12072-018-9919-1] [PMID: 30600478]
[6]
Craig, A.J.; von Felden, J.; Garcia-Lezana, T.; Sarcognato, S.; Villanueva, A. Tumour evolution in hepatocellular carcinoma. Nat. Rev. Gastroenterol. Hepatol., 2020, 17(3), 139-152.
[http://dx.doi.org/10.1038/s41575-019-0229-4] [PMID: 31792430]
[http://dx.doi.org/10.1038/s41575-019-0229-4] [PMID: 31792430]
[7]
Zhang, Z.M.; Wang, J.S.; Zulfiqar, H.; Lv, H.; Dao, F.Y.; Lin, H. Early diagnosis of pancreatic ductal adenocarcinoma by combining relative expression orderings with machine-learning method. Front. Cell Dev. Biol., 2020, 8, 582864.
[http://dx.doi.org/10.3389/fcell.2020.582864] [PMID: 33178697]
[http://dx.doi.org/10.3389/fcell.2020.582864] [PMID: 33178697]
[8]
Zhang, Z.M.; Tan, J.X.; Wang, F.; Dao, F.Y.; Zhang, Z.Y.; Lin, H. Early diagnosis of hepatocellular carcinoma using machine learning method. Front. Bioeng. Biotechnol., 2020, 8, 254.
[http://dx.doi.org/10.3389/fbioe.2020.00254] [PMID: 32292778]
[http://dx.doi.org/10.3389/fbioe.2020.00254] [PMID: 32292778]
[9]
Lorusso, G.; Rüegg, C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem. Cell Biol., 2008, 130(6), 1091-1103.
[http://dx.doi.org/10.1007/s00418-008-0530-8] [PMID: 18987874]
[http://dx.doi.org/10.1007/s00418-008-0530-8] [PMID: 18987874]
[10]
Liu, Y.; Zhou, H.; Zheng, J.; Zeng, X.; Yu, W.; Liu, W.; Huang, G.; Zhang, Y.; Fu, W. Identification of immune-related prognostic biomarkers based on the tumor microenvironment in 20 malignant tumor types with poor prognosis. Front. Oncol., 2020, 10, 1008.
[http://dx.doi.org/10.3389/fonc.2020.01008] [PMID: 32903590]
[http://dx.doi.org/10.3389/fonc.2020.01008] [PMID: 32903590]
[11]
Li, X.; Gao, Y.; Xu, Z.; Zhang, Z.; Zheng, Y.; Qi, F. Identification of prognostic genes in adrenocortical carcinoma microenvironment based on bioinformatic methods. Cancer Med., 2020, 9(3), 1161-1172.
[http://dx.doi.org/10.1002/cam4.2774] [PMID: 31856409]
[http://dx.doi.org/10.1002/cam4.2774] [PMID: 31856409]
[12]
Ng, H.H.M.; Lee, R.Y.; Goh, S.; Tay, I.S.Y.; Lim, X.; Lee, B.; Chew, V.; Li, H.; Tan, B.; Lim, S.; Lim, J.C.T.; Au, B.; Loh, J.J.H.; Saraf, S.; Connolly, J.E.; Loh, T.; Leow, W.Q.; Lee, J.J.X.; Toh, H.C.; Malavasi, F.; Lee, S.Y.; Chow, P.; Newell, E.W.; Choo, S.P.; Tai, D.; Yeong, J.; Lim, T.K.H. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. J. Immunother. Cancer, 2020, 8(2), e000987.
[http://dx.doi.org/10.1136/jitc-2020-000987] [PMID: 32847986]
[http://dx.doi.org/10.1136/jitc-2020-000987] [PMID: 32847986]
[13]
Huang, K.; Zhang, P.; Zhang, Z.; Youn, J.Y.; Wang, C.; Zhang, H.; Cai, H. Traditional Chinese Medicine (TCM) in the treatment of COVID-19 and other viral infections: Efficacies and mechanisms. Pharmacol. Ther., 2021, 225, 107843.
[http://dx.doi.org/10.1016/j.pharmthera.2021.107843] [PMID: 33811957]
[http://dx.doi.org/10.1016/j.pharmthera.2021.107843] [PMID: 33811957]
[14]
Riera-Domingo, C.; Audigé, A.; Granja, S.; Cheng, W.C.; Ho, P.C.; Baltazar, F.; Stockmann, C.; Mazzone, M. Immunity, hypoxia, and metabolism–the ménage à trois of cancer: implications for immunotherapy. Physiol. Rev., 2020, 100(1), 1-102.
[http://dx.doi.org/10.1152/physrev.00018.2019] [PMID: 31414610]
[http://dx.doi.org/10.1152/physrev.00018.2019] [PMID: 31414610]
[15]
Gilkes, D.M.; Semenza, G.L.; Wirtz, D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat. Rev. Cancer, 2014, 14(6), 430-439.
[http://dx.doi.org/10.1038/nrc3726] [PMID: 24827502]
[http://dx.doi.org/10.1038/nrc3726] [PMID: 24827502]
[16]
Rankin, E.B.; Giaccia, A.J. Hypoxic control of metastasis. Science, 2016, 352(6282), 175-180.
[http://dx.doi.org/10.1126/science.aaf4405] [PMID: 27124451]
[http://dx.doi.org/10.1126/science.aaf4405] [PMID: 27124451]
[17]
Zhang, Y.; Liu, T.; Wang, J.; Zou, B.; Li, L.; Yao, L.; Chen, K.; Ning, L.; Wu, B.; Zhao, X.; Wang, D. Cellinker: a platform of ligand–receptor interactions for intercellular communication analysis. Bioinformatics, 2021, 37(14), 2025-2032.
[http://dx.doi.org/10.1093/bioinformatics/btab036] [PMID: 33471060]
[http://dx.doi.org/10.1093/bioinformatics/btab036] [PMID: 33471060]
[18]
Wang, J.; Zhang, Y.; Shen, X.; Zhu, J.; Zhang, L.; Zou, J.; Guo, Z. Finding co-mutated genes and candidate cancer genes in cancer genomes by stratified false discovery rate control. Mol. Biosyst., 2011, 7(4), 1158-1166.
[http://dx.doi.org/10.1039/c0mb00211a] [PMID: 21279201]
[http://dx.doi.org/10.1039/c0mb00211a] [PMID: 21279201]
[19]
Ma, B.; Cheng, H.; Mu, C.; Geng, G.; Zhao, T.; Luo, Q.; Ma, K.; Chang, R.; Liu, Q.; Gao, R.; Nie, J.; Xie, J.; Han, J.; Chen, L.; Ma, G.; Zhu, Y.; Chen, Q. The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Nat. Commun., 2019, 10(1), 1034.
[http://dx.doi.org/10.1038/s41467-019-08618-y] [PMID: 30833558]
[http://dx.doi.org/10.1038/s41467-019-08618-y] [PMID: 30833558]
[20]
Zhou, Y.; Zhou, B.; Pache, L.; Chang, M.; Khodabakhshi, A.H.; Tanaseichuk, O.; Benner, C.; Chanda, S.K. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat. Commun., 2019, 10(1), 1523.
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[http://dx.doi.org/10.1038/s41467-019-09234-6] [PMID: 30944313]
[21]
D'Angelo, G.M.; Rao, D.; Gu, C.C. Combining least absolute
shrinkage and selection operator (LASSO) and principalcomponents
analysis for detection of gene-gene interactions in genome-
wide association studies. BMC Proc, 2009, 3 Suppl 7(Suppl 7), S62.
[22]
Yoshihara, K.; Shahmoradgoli, M.; Martínez, E.; Vegesna, R.; Kim, H.; Torres-Garcia, W.; Treviño, V.; Shen, H.; Laird, P.W.; Levine, D.A.; Carter, S.L.; Getz, G.; Stemke-Hale, K.; Mills, G.B.; Verhaak, R.G.W. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun., 2013, 4(1), 2612.
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[http://dx.doi.org/10.1038/ncomms3612] [PMID: 24113773]
[23]
Newman, A.M.; Liu, C.L.; Green, M.R.; Gentles, A.J.; Feng, W.; Xu, Y.; Hoang, C.D.; Diehn, M.; Alizadeh, A.A. Robust enumeration of cell subsets from tissue expression profiles. Nat. Methods, 2015, 12(5), 453-457.
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[http://dx.doi.org/10.1038/nmeth.3337] [PMID: 25822800]
[24]
Kim, J.E.; Patel, M.A.; Mangraviti, A.; Kim, E.S.; Theodros, D.; Velarde, E.; Liu, A.; Sankey, E.W.; Tam, A.; Xu, H.; Mathios, D.; Jackson, C.M.; Harris-Bookman, S.; Garzon-Muvdi, T.; Sheu, M.; Martin, A.M.; Tyler, B.M.; Tran, P.T.; Ye, X.; Olivi, A.; Taube, J.M.; Burger, P.C.; Drake, C.G.; Brem, H.; Pardoll, D.M.; Lim, M. Combination therapy with Anti-PD-1, Anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin. Cancer Res., 2017, 23(1), 124-136.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1535] [PMID: 27358487]
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1535] [PMID: 27358487]
[25]
Nishino, M.; Ramaiya, N.H.; Hatabu, H.; Hodi, F.S. Monitoring immune-checkpoint blockade: response evaluation and biomarker development. Nat. Rev. Clin. Oncol., 2017, 14(11), 655-668.
[http://dx.doi.org/10.1038/nrclinonc.2017.88] [PMID: 28653677]
[http://dx.doi.org/10.1038/nrclinonc.2017.88] [PMID: 28653677]
[26]
Ruffo, E.; Wu, R.C.; Bruno, T.C.; Workman, C.J.; Vignali, D.A.A. Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor. Semin. Immunol., 2019, 42, 101305.
[http://dx.doi.org/10.1016/j.smim.2019.101305] [PMID: 31604537]
[http://dx.doi.org/10.1016/j.smim.2019.101305] [PMID: 31604537]
[27]
Liu, L.; You, X.; Han, S.; Sun, Y.; Zhang, J.; Zhang, Y. CD155/TIGIT, a novel immune checkpoint in human cancers (Review). Oncol. Rep., 2021, 45(3), 835-845.
[http://dx.doi.org/10.3892/or.2021.7943] [PMID: 33469677]
[http://dx.doi.org/10.3892/or.2021.7943] [PMID: 33469677]
[28]
Addeo, A.; Friedlaender, A.; Banna, G.L.; Weiss, G.J. TMB or not TMB as a biomarker: That is the question. Crit. Rev. Oncol. Hematol., 2021, 163, 103374.
[http://dx.doi.org/10.1016/j.critrevonc.2021.103374] [PMID: 34087341]
[http://dx.doi.org/10.1016/j.critrevonc.2021.103374] [PMID: 34087341]
[29]
Pezzotti, N.; Lelieveldt, B.P.F.; Maaten, L.; Hollt, T.; Eisemann, E.; Vilanova, A. Approximated and user steerable tsne for progressive visual analytics. IEEE Trans. Vis. Comput. Graph., 2017, 23(7), 1739-1752.
[http://dx.doi.org/10.1109/TVCG.2016.2570755] [PMID: 28113434]
[http://dx.doi.org/10.1109/TVCG.2016.2570755] [PMID: 28113434]
[30]
Bao, M.H.R.; Wong, C.C.L. Hypoxia, metabolic reprogramming, and drug resistance in liver cancer. Cells, 2021, 10(7), 1715.
[http://dx.doi.org/10.3390/cells10071715] [PMID: 34359884]
[http://dx.doi.org/10.3390/cells10071715] [PMID: 34359884]
[31]
Gray, L.H.; Conger, A.D.; Ebert, M.; Hornsey, S.; Scott, O.C.A. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol., 1953, 26(312), 638-648.
[http://dx.doi.org/10.1259/0007-1285-26-312-638] [PMID: 13106296]
[http://dx.doi.org/10.1259/0007-1285-26-312-638] [PMID: 13106296]
[32]
Chen, C.; Lou, T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget, 2017, 8(28), 46691-46703.
[http://dx.doi.org/10.18632/oncotarget.17358] [PMID: 28493839]
[http://dx.doi.org/10.18632/oncotarget.17358] [PMID: 28493839]
[33]
Li, J.; Wu, X.; Gan, L.; Yang, X.; Miao, Z. Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells. Acta Pharmacol. Sin., 2017, 38(12), 1642-1654.
[http://dx.doi.org/10.1038/aps.2017.79] [PMID: 28713155]
[http://dx.doi.org/10.1038/aps.2017.79] [PMID: 28713155]
[34]
Zhang, B.; Tang, B.; Gao, J.; Li, J.; Kong, L.; Qin, L. A hypoxia-related signature for clinically predicting diagnosis, prognosis and immune microenvironment of hepatocellular carcinoma patients. J. Transl. Med., 2020, 18(1), 342.
[http://dx.doi.org/10.1186/s12967-020-02492-9] [PMID: 32887635]
[http://dx.doi.org/10.1186/s12967-020-02492-9] [PMID: 32887635]
[35]
Cai, K.; El-Merahbi, R.; Loeffler, M.; Mayer, A.E.; Sumara, G. Ndrg1 promotes adipocyte differentiation and sustains their function. Sci. Rep., 2017, 7(1), 7191.
[http://dx.doi.org/10.1038/s41598-017-07497-x] [PMID: 28775290]
[http://dx.doi.org/10.1038/s41598-017-07497-x] [PMID: 28775290]
[36]
Gon, Y.; Maruoka, S.; Kishi, H.; Kozu, Y.; Kazumichi, K.; Nomura, Y.; Takeshita, I.; Oshima, T.; Hashimoto, S. NDRG1 is important to maintain the integrity of airway epithelial barrier through claudin-9 expression. Cell Biol. Int., 2017, 41(7), 716-725.
[http://dx.doi.org/10.1002/cbin.10741] [PMID: 28191699]
[http://dx.doi.org/10.1002/cbin.10741] [PMID: 28191699]
[37]
Cheng, J.; Xie, H.Y.; Xu, X.; Wu, J.; Wei, X.; Su, R.; Zhang, W.; Lv, Z.; Zheng, S.; Zhou, L. NDRG1 as a biomarker for metastasis, recurrence and of poor prognosis in hepatocellular carcinoma. Cancer Lett., 2011, 310(1), 35-45.
[http://dx.doi.org/10.1016/j.canlet.2011.06.001] [PMID: 21763068]
[http://dx.doi.org/10.1016/j.canlet.2011.06.001] [PMID: 21763068]
[38]
Ai, R.; Sun, Y.; Guo, Z.; Wei, W.; Zhou, L.; Liu, F.; Hendricks, D.T.; Xu, Y.; Zhao, X. NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway. Cancer Biol. Ther., 2016, 17(9), 943-954.
[http://dx.doi.org/10.1080/15384047.2016.1210734] [PMID: 27414086]
[http://dx.doi.org/10.1080/15384047.2016.1210734] [PMID: 27414086]
[39]
Luo, Q.; Wang, C.Q.; Yang, L.Y.; Gao, X.M.; Sun, H.T.; Zhang, Y.; Zhang, K.L.; Zhu, Y.; Zheng, Y.; Sheng, Y.Y.; Lu, L.; Jia, H.L.; Yu, W.Q.; Liu, J.; Dong, Q.Z.; Qin, L.X. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett., 2018, 417, 21-34.
[http://dx.doi.org/10.1016/j.canlet.2017.12.021] [PMID: 29248714]
[http://dx.doi.org/10.1016/j.canlet.2017.12.021] [PMID: 29248714]
[40]
Piast, M.; Kustrzeba-Wójcicka, I.; Matusiewicz, M.; Banaś, T. Molecular evolution of enolase. Acta Biochim. Pol., 2005, 52(2), 507-513.
[http://dx.doi.org/10.18388/abp.2005_3466] [PMID: 15912209]
[http://dx.doi.org/10.18388/abp.2005_3466] [PMID: 15912209]
[41]
Díaz-Ramos, À.; Roig-Borrellas, A.; García-Melero, A.; López-Alemany, R. α-Enolase, a multifunctional protein: its role on pathophysiological situations. J. Biomed. Biotechnol., 2012, 2012, 1-12.
[http://dx.doi.org/10.1155/2012/156795] [PMID: 23118496]
[http://dx.doi.org/10.1155/2012/156795] [PMID: 23118496]
[42]
Li, L.; Liang, Y.; Kang, L.; Liu, Y.; Gao, S.; Chen, S.; Li, Y.; You, W.; Dong, Q.; Hong, T.; Yan, Z.; Jin, S.; Wang, T.; Zhao, W.; Mai, H.; Huang, J.; Han, X.; Ji, Q.; Song, Q.; Yang, C.; Zhao, S.; Xu, X.; Ye, Q. Transcriptional regulation of the warburg effect in cancer by SIX1. Cancer Cell, 2018, 33(3), 368-385.e7.
[http://dx.doi.org/10.1016/j.ccell.2018.01.010] [PMID: 29455928]
[http://dx.doi.org/10.1016/j.ccell.2018.01.010] [PMID: 29455928]
[43]
Capello, M.; Ferri-Borgogno, S.; Riganti, C.; Chattaragada, M.S.; Principe, M.; Roux, C.; Zhou, W.; Petricoin, E.F.; Cappello, P.; Novelli, F. Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest. Oncotarget, 2016, 7(5), 5598-5612.
[http://dx.doi.org/10.18632/oncotarget.6798] [PMID: 26734996]
[http://dx.doi.org/10.18632/oncotarget.6798] [PMID: 26734996]
[44]
Zhou, J.; Zhang, S.; Chen, Z.; He, Z.; Xu, Y.; Li, Z. CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis., 2019, 10(12), 885.
[http://dx.doi.org/10.1038/s41419-019-2127-7] [PMID: 31767835]
[http://dx.doi.org/10.1038/s41419-019-2127-7] [PMID: 31767835]
[45]
Principe, M.; Borgoni, S.; Cascione, M.; Chattaragada, M.S.; Ferri-Borgogno, S.; Capello, M.; Bulfamante, S.; Chapelle, J.; Di Modugno, F.; Defilippi, P.; Nisticò, P.; Cappello, P.; Riganti, C.; Leporatti, S.; Novelli, F. Alpha-enolase (ENO1) controls alpha v/beta 3 integrin expression and regulates pancreatic cancer adhesion, invasion, and metastasis. J. Hematol. Oncol., 2017, 10(1), 16.
[http://dx.doi.org/10.1186/s13045-016-0385-8] [PMID: 28086938]
[http://dx.doi.org/10.1186/s13045-016-0385-8] [PMID: 28086938]
[46]
Qiao, G.; Xu, H.; Li, C.; Li, X.; Farooqi, A.; Zhao, Y.; Liu, X.; Liu, M.; Stagos, D.; Lin, X.; Granulin, A. Granulin a synergizes with cisplatin to inhibit the growth of human hepatocellular carcinoma. Int. J. Mol. Sci., 2018, 19(10), 3060.
[http://dx.doi.org/10.3390/ijms19103060] [PMID: 30301274]
[http://dx.doi.org/10.3390/ijms19103060] [PMID: 30301274]
[47]
Ray, A.; Song, Y.; Du, T.; Chauhan, D.; Anderson, K.C. Preclinical validation of Alpha-Enolase (ENO1) as a novel immunometabolic target in multiple myeloma. Oncogene, 2020, 39(13), 2786-2796.
[http://dx.doi.org/10.1038/s41388-020-1172-0] [PMID: 32024967]
[http://dx.doi.org/10.1038/s41388-020-1172-0] [PMID: 32024967]
[48]
Huang, Y.; Wang, J.; Zhao, Y.; Wang, H.; Liu, T.; Li, Y.; Cui, T.; Li, W.; Feng, Y.; Luo, J.; Gong, J.; Ning, L.; Zhang, Y.; Wang, D.; Zhang, Y. cncRNAdb: a manually curated resource of experimentally supported RNAs with both protein-coding and noncoding function. Nucleic Acids Res., 2021, 49(D1), D65-D70.
[http://dx.doi.org/10.1093/nar/gkaa791] [PMID: 33010163]
[http://dx.doi.org/10.1093/nar/gkaa791] [PMID: 33010163]
[49]
Expression of Concern. Targetting an LncRNA P5848-ENO1 axis inhibits tumor growth in hepatocellular carcinoma. Biosci. Rep., 2020, 40(8), BSR-20180896_EOC.
[http://dx.doi.org/10.1042/BSR-20180896_EOC] [PMID: 32776151]
[http://dx.doi.org/10.1042/BSR-20180896_EOC] [PMID: 32776151]
[50]
Ren, L.; Xu, Y.; Ning, L.; Pan, X.; Li, Y.; Zhao, Q.; Pang, B.; Huang, J.; Deng, K.; Zhang, Y. TCM2COVID: A resource of anti‐COVID‐19 traditional Chinese medicine with effects and mechanisms. iMeta, 2022, e42.
[http://dx.doi.org/10.1002/imt2.42] [PMID: 36245702]
[http://dx.doi.org/10.1002/imt2.42] [PMID: 36245702]
[51]
Yu, S.; Li, N.; Huang, Z.; Chen, R.; Yi, P.; Kang, R.; Tang, D.; Hu, X.; Fan, X. A novel lncRNA, TCONS_00006195, represses hepatocellular carcinoma progression by inhibiting enzymatic activity of ENO1. Cell Death Dis., 2018, 9(12), 1184.
[http://dx.doi.org/10.1038/s41419-018-1231-4] [PMID: 30518748]
[http://dx.doi.org/10.1038/s41419-018-1231-4] [PMID: 30518748]
[52]
Zhu, W.; Li, H.; Yu, Y.; Chen, J.; Chen, X.; Ren, F.; Ren, Z.; Cui, G. Enolase-1 serves as a biomarker of diagnosis and prognosis in hepatocellular carcinoma patients. Cancer Manag. Res., 2018, 10, 5735-5745.
[http://dx.doi.org/10.2147/CMAR.S182183] [PMID: 30532594]
[http://dx.doi.org/10.2147/CMAR.S182183] [PMID: 30532594]
[53]
Adammek, M.; Greve, B.; Kässens, N.; Schneider, C.; Brüggemann, K.; Schüring, A.N.; Starzinski-Powitz, A.; Kiesel, L.; Götte, M. MicroRNA miR-145 inhibits proliferation, invasiveness, and stem cell phenotype of an in vitro endometriosis model by targeting multiple cytoskeletal elements and pluripotency factors. Fertil. Steril., 2013, 99(5), 1346-1355.e5.
[http://dx.doi.org/10.1016/j.fertnstert.2012.11.055] [PMID: 23312222]
[http://dx.doi.org/10.1016/j.fertnstert.2012.11.055] [PMID: 23312222]
[54]
Matsuzaki, K.; Murata, M.; Yoshida, K.; Sekimoto, G.; Uemura, Y.; Sakaida, N.; Kaibori, M.; Kamiyama, Y.; Nishizawa, M.; Fujisawa, J.; Okazaki, K.; Seki, T. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor β signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology, 2007, 46(1), 48-57.
[http://dx.doi.org/10.1002/hep.21672] [PMID: 17596875]
[http://dx.doi.org/10.1002/hep.21672] [PMID: 17596875]
[55]
Boye, A.; Kan, H.; Wu, C.; Jiang, Y.; Yang, X.; He, S.; Yang, Y. MAPK inhibitors differently modulate TGF-β/Smad signaling in HepG2 cells. Tumour Biol., 2015, 36(5), 3643-3651.
[http://dx.doi.org/10.1007/s13277-014-3002-x] [PMID: 25560488]
[http://dx.doi.org/10.1007/s13277-014-3002-x] [PMID: 25560488]
[56]
Li, L.M.; Chen, C.; Ran, R.X.; Huang, J.T.; Sun, H.L.; Zeng, C.; Zhang, Z.; Zhang, W.; Liu, S.M. Loss of TARBP2 drives the progression of hepatocellular carcinoma via miR-145-SERPINE1 Axis. Front. Oncol., 2021, 11, 620912.
[http://dx.doi.org/10.3389/fonc.2021.620912] [PMID: 34249676]
[http://dx.doi.org/10.3389/fonc.2021.620912] [PMID: 34249676]
[57]
Wang, Z.; Huang, D.; Huang, J.; Nie, K.; Li, X.; Yang, X. lncRNA TMPO-AS1 exerts oncogenic roles in hcc through regulating miR-320a/SERBP1 Axis. OncoTargets Ther., 2020, 13, 6539-6551.
[http://dx.doi.org/10.2147/OTT.S250355] [PMID: 32753892]
[http://dx.doi.org/10.2147/OTT.S250355] [PMID: 32753892]
[58]
Li, G.; Du, P.; He, J.; Li, Y. CircRNA circBACH1 (hsa_circ_0061395) serves as a miR-656–3p sponge to facilitate hepatocellular carcinoma progression through increasing SERBP1 expression. Biochem. Biophys. Res. Commun., 2021, 556, 1-8.
[http://dx.doi.org/10.1016/j.bbrc.2021.03.136] [PMID: 33831787]
[http://dx.doi.org/10.1016/j.bbrc.2021.03.136] [PMID: 33831787]
[59]
Liu, Z.; Xu, Y.; Zhang, W.; Gao, X.; Luo, G.; Song, H.; Liu, J.; Wang, H. Identification of targets of JS-K against HBV-positive human hepatocellular carcinoma HepG2.2.15 cells with iTRAQ proteomics. Sci. Rep., 2021, 11(1), 10381.
[http://dx.doi.org/10.1038/s41598-021-90001-3] [PMID: 34001947]
[http://dx.doi.org/10.1038/s41598-021-90001-3] [PMID: 34001947]
[60]
Gerke, V.; Moss, S.E. Annexins: From structure to function. Physiol. Rev., 2002, 82(2), 331-371.
[http://dx.doi.org/10.1152/physrev.00030.2001] [PMID: 11917092]
[http://dx.doi.org/10.1152/physrev.00030.2001] [PMID: 11917092]
[61]
Zhang, H.J.; Yao, D.F.; Yao, M.; Huang, H.; Wu, W.; Yan, M.J.; Yan, X.D.; Chen, J. Expression characteristics and diagnostic value of annexin A2 in hepatocellular carcinoma. World J. Gastroenterol., 2012, 18(41), 5897-5904.
[http://dx.doi.org/10.3748/wjg.v18.i41.5897] [PMID: 23139605]
[http://dx.doi.org/10.3748/wjg.v18.i41.5897] [PMID: 23139605]
[62]
Sun, Y.; Gao, G.; Cai, J.; Wang, Y.; Qu, X.; He, L.; Liu, F.; Zhang, Y.; Lin, K.; Ma, S.; Yang, X.; Qian, X.; Zhao, X. Annexin A2 is a discriminative serological candidate in early hepatocellular carcinoma. Carcinogenesis, 2013, 34(3), 595-604.
[http://dx.doi.org/10.1093/carcin/bgs372] [PMID: 23188673]
[http://dx.doi.org/10.1093/carcin/bgs372] [PMID: 23188673]
[63]
Zhang, H.; Yao, M.; Wu, W.; Qiu, L.; Sai, W.; Yang, J.; Zheng, W.; Huang, J.; Yao, D. Up-regulation of annexin A2 expression predicates advanced clinicopathological features and poor prognosis in hepatocellular carcinoma. Tumour Biol., 2015, 36(12), 9373-9383.
[http://dx.doi.org/10.1007/s13277-015-3678-6] [PMID: 26109000]
[http://dx.doi.org/10.1007/s13277-015-3678-6] [PMID: 26109000]
[64]
Tang, L.; Liu, J.X.; Zhang, Z.J.; Xu, C.Z.; Zhang, X.N.; Huang, W.R.; Zhou, D.H.; Wang, R.R.; Chen, X.D.; Xiao, M.B.; Qu, L.S.; Lu, C.H. High expression of Anxa2 and Stat3 promote progression of hepatocellular carcinoma and predict poor prognosis. Pathol. Res. Pract., 2019, 215(6), 152386.
[http://dx.doi.org/10.1016/j.prp.2019.03.015] [PMID: 30935762]
[http://dx.doi.org/10.1016/j.prp.2019.03.015] [PMID: 30935762]
[65]
Shi, H.; Xiao, L.; Duan, W.; He, H.; Ma, L.; Da, M.; Duan, Y.; Wang, Q.; Wu, H.; Song, X.; Hou, Y. ANXA2 enhances the progression of hepatocellular carcinoma via remodeling the cell motility associated structures. Micron, 2016, 85, 26-33.
[http://dx.doi.org/10.1016/j.micron.2016.03.008] [PMID: 27060670]
[http://dx.doi.org/10.1016/j.micron.2016.03.008] [PMID: 27060670]
[66]
Qiu, L.W.; Liu, Y.F.; Cao, X.Q.; Wang, Y.; Cui, X.H.; Ye, X.; Huang, S.W.; Xie, H.J.; Zhang, H.J. Annexin A2 promotion of hepatocellular carcinoma tumorigenesis via the immune microenvironment. World J. Gastroenterol., 2020, 26(18), 2126-2137.
[http://dx.doi.org/10.3748/wjg.v26.i18.2126] [PMID: 32476780]
[http://dx.doi.org/10.3748/wjg.v26.i18.2126] [PMID: 32476780]
[67]
Chiu, D.K.C.; Tse, A.P.W.; Xu, I.M.J.; Di Cui, J.; Lai, R.K.H.; Li, L.L.; Koh, H.Y.; Tsang, F.H.C.; Wei, L.L.; Wong, C.M.; Ng, I.O.L.; Wong, C.C.L. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat. Commun., 2017, 8(1), 517.
[http://dx.doi.org/10.1038/s41467-017-00530-7] [PMID: 28894087]
[http://dx.doi.org/10.1038/s41467-017-00530-7] [PMID: 28894087]
[68]
Duan, H.; Liu, Y.; Gao, Z.; Huang, W. Recent advances in drug delivery systems for targeting cancer stem cells. Acta Pharm. Sin. B, 2021, 11(1), 55-70.
[http://dx.doi.org/10.1016/j.apsb.2020.09.016] [PMID: 33532180]
[http://dx.doi.org/10.1016/j.apsb.2020.09.016] [PMID: 33532180]
[69]
Chang, C.H.; Qiu, J.; O’Sullivan, D.; Buck, M.D.; Noguchi, T.; Curtis, J.D.; Chen, Q.; Gindin, M.; Gubin, M.M.; van der Windt, G.J.W.; Tonc, E.; Schreiber, R.D.; Pearce, E.J.; Pearce, E.L. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell, 2015, 162(6), 1229-1241.
[http://dx.doi.org/10.1016/j.cell.2015.08.016] [PMID: 26321679]
[http://dx.doi.org/10.1016/j.cell.2015.08.016] [PMID: 26321679]
[70]
Ho, P.C.; Bihuniak, J.D.; Macintyre, A.N.; Staron, M.; Liu, X.; Amezquita, R.; Tsui, Y.C.; Cui, G.; Micevic, G.; Perales, J.C.; Kleinstein, S.H.; Abel, E.D.; Insogna, K.L.; Feske, S.; Locasale, J.W.; Bosenberg, M.W.; Rathmell, J.C.; Kaech, S.M. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell, 2015, 162(6), 1217-1228.
[http://dx.doi.org/10.1016/j.cell.2015.08.012] [PMID: 26321681]
[http://dx.doi.org/10.1016/j.cell.2015.08.012] [PMID: 26321681]
[71]
Chiossone, L.; Dumas, P.Y.; Vienne, M.; Vivier, E. Natural killer cells and other innate lymphoid cells in cancer. Nat. Rev. Immunol., 2018, 18(11), 671-688.
[http://dx.doi.org/10.1038/s41577-018-0061-z] [PMID: 30209347]
[http://dx.doi.org/10.1038/s41577-018-0061-z] [PMID: 30209347]
[72]
Tian, X.; Wu, Y.; Yang, Y.; Wang, J.; Niu, M.; Gao, S.; Qin, T.; Bao, D. Long noncoding RNA LINC00662 promotes M2 macrophage polarization and hepatocellular carcinoma progression via activating Wnt/β‐catenin signaling. Mol. Oncol., 2020, 14(2), 462-483.
[http://dx.doi.org/10.1002/1878-0261.12606] [PMID: 31785055]
[http://dx.doi.org/10.1002/1878-0261.12606] [PMID: 31785055]
[73]
Li, C.; Pan, X.Y.; Ma, M.; Zhao, J.; Zhao, F.; Lv, Y.P. Astragalus polysacharin inhibits hepatocellular carcinoma-like phenotypes in a murine HCC model through repression of M2 polarization of tumour-associated macrophages. Pharm. Biol., 2021, 59(1), 1531-1537.
[http://dx.doi.org/10.1080/13880209.2021.1991384] [PMID: 34726570]
[http://dx.doi.org/10.1080/13880209.2021.1991384] [PMID: 34726570]
