Clinical Significance of Mitogen-activated Protein Kinase Kinase Kinases in Hepatitis B Virus -related Hepatocellular Carcinoma and Underlying Mechanism Exploration

Overview

Journal Bioengineered

Date 2022 Mar 21

PMID 35311629

Authors

Zhengqian Liu

Xin Zhou

Peng Zheng

Chenheng Bu

Xiaoou Yan

Haizhou Yu

Yong Xu

Affiliations

Soon will be listed here.

Abstract

The purpose of this research was to explore the diagnostic/prognostic significance and prospective molecular mechanisms of mitogen-activated protein kinase kinase kinases () in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Diagnostic/prognostic significance of was screened in the GSE1450 data set and validated in the Guangxi cohort. Various bioinformatics tools were used to explore the biological functions of prognosis-related genes. Subsequently, molecular biology assays were used to verify the biological functions and molecular mechanisms of specific gene. was observed to be differentially expressed in HCC and adjacent tissues with satisfactory diagnostic value. It was discovered in survival analysis that and were associated with overall survival (OS) of patients with HBV-related HCC in the GSE1450 data set and the Guangxi cohort. Nomograms were established based on prognosis-related genes and clinical factors for individualized risk assessment. The assays on HCC cells demonstrated that MAP3K13 regulated the death and proliferation of HCC cells by activating the JNK pathway and inducing the expression of apoptosis-related factors. In conclusion, our results suggested that might serve as a diagnostic biomarker in HBV-related HCC and and might serve as useful prognostic biomarkers. Besides, cytological assays prompted that MAP3K13 might impact the prognosis of HCC by regulating the JNK pathway and inducing apoptosis.

References

English J, Pearson G, Wilsbacher J, Swantek J, Karandikar M, Xu S . New insights into the control of MAP kinase pathways. Exp Cell Res. 1999; 253(1):255-70. DOI: 10.1006/excr.1999.4687. View

Avruch J, Khokhlatchev A, Kyriakis J, Luo Z, Tzivion G, Vavvas D . Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade. Recent Prog Horm Res. 2001; 56:127-55. DOI: 10.1210/rp.56.1.127. View

Inokuchi S, Aoyama T, Miura K, Osterreicher C, Kodama Y, Miyai K . Disruption of TAK1 in hepatocytes causes hepatic injury, inflammation, fibrosis, and carcinogenesis. Proc Natl Acad Sci U S A. 2010; 107(2):844-9. PMC: 2818947. DOI: 10.1073/pnas.0909781107. View

Keshet Y, Seger R . The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol. 2010; 661:3-38. DOI: 10.1007/978-1-60761-795-2_1. View

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View

Cao J, Zhang C, Jiang G, Jin S, Wang Q, Wang A . Identification of hepatocellular carcinoma-related genes associated with macrophage differentiation based on bioinformatics analyses. Bioengineered. 2020; 12(1):296-309. PMC: 8806327. DOI: 10.1080/21655979.2020.1868119. View

Cougot D, Neuveut C, Buendia M . HBV induced carcinogenesis. J Clin Virol. 2006; 34 Suppl 1:S75-8. DOI: 10.1016/s1386-6532(05)80014-9. View

Chen W, Zheng R, Baade P, Zhang S, Zeng H, Bray F . Cancer statistics in China, 2015. CA Cancer J Clin. 2016; 66(2):115-32. DOI: 10.3322/caac.21338. View

Kan Z, Zheng H, Liu X, Li S, Barber T, Gong Z . Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma. Genome Res. 2013; 23(9):1422-33. PMC: 3759719. DOI: 10.1101/gr.154492.113. View

10.

Cargnello M, Roux P . Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011; 75(1):50-83. PMC: 3063353. DOI: 10.1128/MMBR.00031-10. View

11.

Wang X, Liao X, Zhou X, Han C, Chen Z, Yang C . Oncogene enhances cellular invasion, migration and proliferation abilities via autophagy-related pathway resulting in poor prognosis in hepatocellular carcinoma. Am J Cancer Res. 2021; 10(12):4178-4197. PMC: 7783760. View

12.

Masaki M, Ikeda A, Shiraki E, Oka S, Kawasaki T . Mixed lineage kinase LZK and antioxidant protein-1 activate NF-kappaB synergistically. Eur J Biochem. 2002; 270(1):76-83. DOI: 10.1046/j.1432-1033.2003.03363.x. View

13.

Wang G, Bai X, Jiang G, Jin S, Wang Q, Wang A . GIT1 overexpression promotes epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma. Bioengineered. 2020; 12(1):30-43. PMC: 8806235. DOI: 10.1080/21655979.2020.1855914. View

14.

Mandic A, Bennek E, Verdier J, Zhang K, Roubrocks S, Davis R . c-Jun N-terminal kinase 2 promotes enterocyte survival and goblet cell differentiation in the inflamed intestine. Mucosal Immunol. 2017; 10(5):1211-1223. DOI: 10.1038/mi.2016.125. View

15.

Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu M, Allen C . The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol. 2017; 3(12):1683-1691. PMC: 5824275. DOI: 10.1001/jamaoncol.2017.3055. View

16.

Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F . TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell. 2010; 17(5):481-96. DOI: 10.1016/j.ccr.2010.03.021. View

17.

Han H, Chen Y, Cheng L, Prochownik E, Li Y . microRNA-206 impairs c-Myc-driven cancer in a synthetic lethal manner by directly inhibiting MAP3K13. Oncotarget. 2016; 7(13):16409-19. PMC: 4941324. DOI: 10.18632/oncotarget.7653. View

18.

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

19.

Ikeda A, Hasegawa K, Masaki M, Moriguchi T, Nishida E, Kozutsumi Y . Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway. J Biochem. 2001; 130(6):773-81. DOI: 10.1093/oxfordjournals.jbchem.a003048. View

20.

Heagerty P, Zheng Y . Survival model predictive accuracy and ROC curves. Biometrics. 2005; 61(1):92-105. DOI: 10.1111/j.0006-341X.2005.030814.x. View