Abstract
Purpose
Chronic hepatitis B-liver cirrhosis-hepatocellular carcinoma (CLH), commonly called the “liver cancer trilogy”, is a crucial evolutionary phase in the emergence of hepatocellular carcinoma (HCC) in China. Previous studies on early diagnostic biomarkers of HCC were limited to the end-stage of HCC and did not focus on the evolutionary process of CLH.
Methods
11 monotonically changing differentially expressed genes (MCDEGs) highly correlated with CLH were screened through bioinformatic analysis and KPNA2 was identified for further research. The serum KPNA2 expression in different CLH states was detected by Enzyme linked immunosorbent assay (ELISA). A nomogram model was constructed using univariate and multivariate Cox regression methods.
Results
The single-cell RNA-seq and bulk RNA-seq revealed that KPNA2 related to immune infiltration in HCC and may participate in cell cycle pathways in HCC. The serum KPNA2 expression was monotonically upregulated in CLH and was valuable for diagnosing different CLH states. Besides, chronic hepatitis B(CHB) patients, liver cirrhosis (LC) patients, and HCC patients were classified into subgroups with distinct serum KPNA2 expressions. Accordingly, patients with different serum KPNA2 expressions displayed various clinicopathological features. The AUC value of the nomogram model was 0.959 in predicting the likelihood of developing HCC in CHB patients or LC patients. Finally, we found that KPNA2 expression was negatively correlated with the IC50 of four chemotherapeutic drugs in HCC.
Conclusion
KPNA2 was a novel serum biomarker for diagnosing different CLH states, monitoring the dynamic evolution of CLH, and a new therapeutic target for intervening in the progression of CLH.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author. Publicly available datasets were analyzed in this study. This data can be found here: https://portal.gdc.cancer.gov/, and http://www.ncbi.nlm.nih.gov/geo/.
References
Ballard DH (2023) Microvascular invasion in hepatocellular carcinoma: bridging the global gap between imaging and clinical practice. Acad Radiol. https://doi.org/10.1016/j.acra.2023.05.017
Cai X, Tang D, Chen J et al (2023) Evaluation of serum FGL1 as diagnostic markers for hbv-related hepatocellular carcinoma. Lab Med 54:270–281. https://doi.org/10.1093/labmed/lmac094
Cassany A, Guillemain G, Klein C et al (2004) A karyopherin alpha2 nuclear transport pathway is regulated by glucose in hepatic and pancreatic cells. Traffic 5:10–19. https://doi.org/10.1046/j.1398-9219.2003.0143.x
Chen T, Liu R, Niu Y et al (2021) HIF-1α-activated long non-coding RNA KDM4A-AS1 promotes hepatocellular carcinoma progression via the miR-411–5p/KPNA2/AKT pathway. Cell Death Dis 12:1152. https://doi.org/10.1038/s41419-021-04449-2
Christiansen A, Dyrskjøt L (2013) The functional role of the novel biomarker karyopherin α 2 (KPNA2) in cancer. Cancer Lett 331:18–23. https://doi.org/10.1016/j.canlet.2012.12.013
Dalbeni A, Natola LA, Garbin M et al (2023) Interleukin-6: a new marker of advanced-sarcopenic HCC cirrhotic patients. Cancers (basel) 15:2406. https://doi.org/10.3390/cancers15092406
Drucker E, Holzer K, Pusch S et al (2019) Karyopherin α2-dependent import of E2F1 and TFDP1 maintains protumorigenic stathmin expression in liver cancer. Cell Commun Signal 17:159. https://doi.org/10.1186/s12964-019-0456-x
Gao CL, Wang GW, Yang GQ et al (2018) Karyopherin subunit-α 2 expression accelerates cell cycle progression by upregulating CCNB2 and CDK1 in hepatocellular carcinoma. Oncol Lett 15:2815–2820. https://doi.org/10.3892/ol.2017.7691
Ghahremanloo A, Soltani A, Modaresi SMS et al (2019) Recent advances in the clinical development of immune checkpoint blockade therapy. Cell Oncol (dordr) 42:609–626. https://doi.org/10.1007/s13402-019-00456-w
Guo X, Wang Z, Zhang J et al (2019) Upregulated KPNA2 promotes hepatocellular carcinoma progression and indicates prognostic significance across human cancer types. Acta Biochim Biophys Sin (shanghai) 51:285–292. https://doi.org/10.1093/abbs/gmz003
Han Y, Wang X (2020) The emerging roles of KPNA2 in cancer. Life Sci 241:117140. https://doi.org/10.1016/j.lfs.2019.117140
Hanzelmann S, Castelo R, Guinney J (2013) GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14:7. https://doi.org/10.1186/1471-2105-14-7
He X, Xu C (2020) Immune checkpoint signaling and cancer immunotherapy. Cell Res 30:660–669. https://doi.org/10.1038/s41422-020-0343-4
Hsu YC, Huang DQ, Nguyen MH (2023) Global burden of hepatitis B virus: current status, missed opportunities and a call for action. Nat Rev Gastroenterol Hepatol. https://doi.org/10.1038/s41575-023-00760-9
Huang Z, Zhou P, Li S et al (2022) Prediction of the Ki-67 marker index in hepatocellular carcinoma based on dynamic contrast-enhanced ultrasonography with sonazoid. Insights Imaging 13:199. https://doi.org/10.1186/s13244-022-01320-6
Jiang P, Tang Y, He L et al (2014) Aberrant expression of nuclear KPNA2 is correlated with early recurrence and poor prognosis in patients with small hepatocellular carcinoma after hepatectomy. Med Oncol 31:131. https://doi.org/10.1007/s12032-014-0131-4
Li X, Sun Y, Jin Y (2008) Identification of karyopherin-alpha 2 as an Oct4 associated protein. J Genet Genom 35:723–728. https://doi.org/10.1016/S1673-8527(08)60227-1
Li T, Fan J, Wang B et al (2017) TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Cancer Res 77:e108–e110. https://doi.org/10.1158/0008-5472
Li HT, Wei B, Li ZQ et al (2020) Diagnostic and prognostic value of MCM3 and its interacting proteins in hepatocellular carcinoma. Oncol Lett 20:308. https://doi.org/10.3892/ol.2020.12171
Liberzon A, Subramanian A, Pinchback R et al (2011) Molecular signatures database (MSigDB) 3.0. Bioinformatics 27(12):1739–1740. https://doi.org/10.1093/bioinformatics/btr260
Lim DH, Casadei-Gardini A, Lee MA et al (2022) Prognostic implication of serum AFP in patients with hepatocellular carcinoma treated with regorafenib. Future Oncol 18:3021–3030. https://doi.org/10.2217/fon-2022-0524
Lin L, Sun J, Tan Y et al (2017) Prognostic implication of NQO1 overexpression in hepatocellular carcinoma. Hum Pathol 69:31–37. https://doi.org/10.1016/j.humpath.2017.09.002
Lin CZ, Ou RW, Hu YH (2018) Lentiviral-mediated microRNA-26b up-regulation inhibits proliferation and migration of hepatocellular carcinoma cells. Kaohsiung J Med Sci 34:547–555. https://doi.org/10.1016/j.kjms.2018.05.00
Malaguarnera G, Giordano M, Paladina I et al (2010) Serum markers of hepatocellular carcinoma. Dig Dis Sci 55:2744–2755. https://doi.org/10.1007/s10620-010-1184-7
Mehraj U, Ganai RA, Macha MA et al (2021) The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: new challenges and therapeutic opportunities. Cell Oncol (dordr) 44:1209–1229. https://doi.org/10.1007/s13402-021-00634-9
Mehta N (2020) Hepatocellular carcinoma-how to determine therapeutic options. Hepatol Commun 4:342–354. https://doi.org/10.1002/hep4.1481
Miao LL, Wang JW, Liu HH et al (2023) Hypomethylation of glycine dehydrogenase promoter in peripheral blood mononuclear cells is a new diagnostic marker of hepatitis B virus-associated hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 23:S1499-3872(23)00034–6. https://doi.org/10.1016/j.hbpd.2023.02.011
Mohamed AS, Abd El Hafez A, Eltantawy A et al (2022) Diagnostic and prognostic value of isolated and combined MCM3 and glypican-3 expression in hepatocellular carcinoma: a novel immunosubtyping prognostic model. Appl Immunohistochem Mol Morphol 30:694–702. https://doi.org/10.1097/PAI.0000000000001080
O’Brien P, Morin P Jr, Ouellette RJ et al (2011) The Pax-5 gene: a pluripotent regulator of B-cell differentiation and cancer disease. Cancer Res 71:7345–7350. https://doi.org/10.1158/0008-5472
Pinter M, Trauner M, Peck-Radosavljevic M et al (2016) Cancer and liver cirrhosis: implications on prognosis and management. ESMO Open 1:e000042. https://doi.org/10.1136/esmoopen-2016-000042
Qu Q, Sawa H, Suzuki T et al (2004) Nuclear entry mechanism of the human polyomavirus JC virus-like particle: role of importins and the nuclear pore complex. J Biol Chem 279:27735–27742. https://doi.org/10.1074/jbc.M310827200
Sakai M, Sohda M, Miyazaki T et al (2010) Significance of karyopherin-{alpha} 2 (KPNA2) expression in esophageal squamous cell carcinoma. Anticancer Res 30:851–856
Stroffolini T, Stroffolini G (2023) A historical overview on the role of hepatitis B and C viruses as aetiological factors for hepatocellular carcinoma. Cancers (basel) 15:2388. https://doi.org/10.3390/cancers15082388
Subramanian A, Tamayo P, Mootha VK et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550. https://doi.org/10.1073/pnas.0506580102
Sung H, Ferlay J, Siegel R et al (2021) global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin 71:209–249. https://doi.org/10.3322/caac.21660
Szklarczyk D, Gable AL, Lyon D et al (2019) STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 47:D607–D613. https://doi.org/10.1093/nar/gky1131
Tanaka T, Taniguchi T, Sannomiya K et al (2013) Novel des-γ-carboxy prothrombin in serum for the diagnosis of hepatocellular carcinoma. J Gastroenterol Hepatol 28:1348–1355. https://doi.org/10.1111/jgh.12166
Wang CI, Wang CL, Wang CW et al (2011) Importin subunit alpha-2 is identified as a potential biomarker for non-small cell lung cancer by integration of the cancer cell secretome and tissue transcriptome. Int J Cancer 128:2364–2372. https://doi.org/10.1002/ijc.25568
Wang JH, Zhong XP, Zhang YF et al (2017) Cezanne predicts progression and adjuvant tace response in hepatocellular carcinoma. Cell Death Dis 8:e3043–e. https://doi.org/10.1038/cddis.2017.428
Wang P, Zhao Y, Liu K et al (2019) Wip1 cooperates with KPNA2 to modulate the cell proliferation and migration of colorectal cancer via a p53-dependent manner. J Cell Biochem 120:15709–15718. https://doi.org/10.1002/jcb.28840
Xu M, Xu K, Yin S et al (2023) In-depth serum proteomics reveals the trajectory of hallmarks of cancer in hepatitis B virus-related liver diseases. Mol Cell Proteomics 22:100574. https://doi.org/10.1016/j.mcpro.2023.100574
Xue W, Wang Y, Xie Y et al (2021) miRNA-based signature associated with tumor mutational burden in colon adenocarcinoma. Front Oncol 11:634841. https://doi.org/10.3389/fonc.2021.634841
Xue W, Dong B, Wang Y et al (2022) A novel prognostic index of stomach adenocarcinoma based on immunogenomic landscape analysis and immunotherapy options. Exp Mol Pathol 128:104832. https://doi.org/10.1016/j.yexmp.2022.104832
Yang W, Soares J, Greninger P et al (2013) Genomics of drug sensitivity in cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 41:D955–D961. https://doi.org/10.1093/nar/gks1111
Yu C, Wang L, Han Y et al (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. Omics A J Integr Biol 16:284–287. https://doi.org/10.1089/omi.2011.0118
Yu B, Liang H, Ye Q et al (2021) Establishment of a genomic-clinicopathologic nomogram for predicting early recurrence of hepatocellular carcinoma after R0 resection. J Gastrointest Surg 25:112–124. https://doi.org/10.1007/s11605-020-04554-1
Zan Y, Wang B, Liang L et al (2019) MicroRNA-139 inhibits hepatocellular carcinoma cell growth through down-regulating karyopherin alpha 2. J Exp Clin Cancer Res 38:182. https://doi.org/10.1186/s13046-019-1175-2
Zhang Y, Zhang M, Yu F et al (2015) Karyopherin alpha 2 is a novel prognostic marker and a potential therapeutic target for colon cancer. J Exp Clin Cancer Res 34:145. https://doi.org/10.1186/s13046-015-0261-3
Zhang J, Zhang X, Wang L et al (2021) Multiomics-based analyses of KPNA2 highlight its multiple potentials in hepatocellular carcinoma. Peer J 9:e12197. https://doi.org/10.7717/peerj.12197
Zhu YH, Zheng JH, Jia QY et al (2023) Immunosuppression, immune escape, and immunotherapy in pancreatic cancer: focused on the tumor microenvironment. Cell Oncol (dordr) 46:17–48. https://doi.org/10.1007/s13402-022-00741-1
Funding
This work was supported by Zhejiang Province Major Science and Technology Project for Medicine and Health, grant number WKJ-ZJ-2329; General Scientific Research Project of Zhejiang Provincial Education Department, grant number Y202250086.
Author information
Authors and Affiliations
Contributions
YP and YZ initiated the study and organized it; YP and ZL designed and carried out bioinformatics analyses, statistical analyses, drew figures, and drafted the manuscript; DJ completed immunohistochemistry experiments, SL contributed to the review and editing. All authors have read and agreed to the published version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The work involving the serum and tissue specimens was reviewed and approved by the Ethics Committee of Wenzhou Medical University Affiliated Zhoushan Hospital. Informed consent was obtained from each patient included in the present study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Pan, Y., Zhang, Y., Lu, Z. et al. The role of KPNA2 as a monotonically changing differentially expressed gene in the diagnosis, risk stratification, and chemotherapy sensitivity of chronic hepatitis B-liver cirrhosis-hepatocellular carcinoma. J Cancer Res Clin Oncol 149, 13753–13771 (2023). https://doi.org/10.1007/s00432-023-05213-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-023-05213-z