Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

MLK3 promotes prooncogenic signaling in hepatocellular carcinoma via TGFβ pathway

Oncogene volume 43, pages 2307–2324 (2024)Cite this article

Subjects

Abstract

Advanced hepatocellular carcinoma (HCC) is a lethal disease, with limited therapeutic options. Mixed Lineage Kinase 3 (MLK3) is a key regulator of liver diseases, although its role in HCC remains unclear. Analysis of TCGA databases suggested elevated MAP3K11 (MLK3 gene) expression, and TMA studies showed higher MLK3 activation in human HCCs. To understand MLK3’s role in HCC, we utlized carcinogen-induced HCC model and compared between wild-type and MLK3 knockout (MLK3−/−) mice. Our studies showed that MLK3 kinase activity is upregulated in HCC, and MLK3 deficiency alleviates HCC progression. MLK3 deficiency reduced proliferation in vivo and MLK3 inhibition reduced proliferation and colony formation in vitro. To obtain further insight into the mechanism and identify newer targets mediating MLK3-induced HCCs, RNA-sequencing analysis was performed. These showed that MLK3 deficiency modulates various gene signatures, including EMT, and reduces TGFB1&2 expressions. HCC cells overexpressing MLK3 promoted EMT via autocrine TGFβ signaling. Moreover, MLK3 deficiency attenuated activated hepatic stellate cell (HSC) signature, which is increased in wild-type. Interestingly, MLK3 promotes HSC activation via paracrine TGFβ signaling. These findings reveal TGFβ playing a key role at different steps of HCC, downstream of MLK3, implying MLK3-TGFβ axis to be an ideal drug target for advanced HCC management.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Upregulation of MAP3K11 mRNA and MLK3 activity in human hepatocellular carcinoma.
Fig. 2: Genetic loss of MLK3 reduces DEN/PB-induced hepatocarcinogenesis and cell proliferation.
Fig. 3: MLK3 regulates proliferation in HCC cell lines.
Fig. 4: Differential transcriptomic profiling of WT and MLK3−/− liver tissue identified MLK3 as an upstream regulator of TGFβ1 and TGFβ2 in DEN/PB-induced HCC.
Fig. 5: MLK3 overexpression promotes epithelial-mesenchymal transition (EMT) in HCC cells.
Fig. 6: MLK3 deficiency reduces DEN/PB induced-HSC activation and collagen expression.
Fig. 7: MLK3-induced TGFβ signaling regulates HCC progression and HSC activation.
Fig. 8: Scheme describing the role of MLK3-TGFβ axis in carcinogen-induced HCC progression.

Similar content being viewed by others

Data availability

The RNA-seq data discussed in this publication has been deposited into the Gene Expression Omnibus (GSE233074). All study data are included in the article and Supplementary Materials.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.

    Article  CAS  PubMed  Google Scholar 

  3. Pinzani M. Epithelial-mesenchymal transition in chronic liver disease: fibrogenesis or escape from death? J Hepatol. 2011;55:459–65.

    Article  CAS  PubMed  Google Scholar 

  4. Ogunwobi OO, Harricharran T, Huaman J, Galuza A, Odumuwagun O, Tan Y, et al. Mechanisms of hepatocellular carcinoma progression. World J Gastroenterol. 2019;25:2279–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rana A, Rana B, Mishra R, Sondarva G, Rangasamy V, Das S, et al. Mixed Lineage Kinase-c-Jun N-Terminal Kinase Axis: A Potential Therapeutic Target in Cancer. Genes Cancer. 2013;4:334–41.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Jiang JX, Torok NJ. MLK3 as a regulator of disease progression in Non-alcoholic steatohepatitis. Liver Int. 2014;34:1131–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tomita K, Kohli R, MacLaurin BL, Hirsova P, Guo Q, Sanchez LHG et al. Mixed-lineage kinase 3 pharmacological inhibition attenuates murine nonalcoholic steatohepatitis. JCI Insight. 2017;2:e94488.

  8. McCullough RL, Saikia P, Pollard KA, McMullen MR, Nagy LE, Roychowdhury S. Myeloid Mixed Lineage Kinase 3 Contributes to Chronic Ethanol-Induced Inflammation and Hepatocyte Injury in Mice. Gene Expr. 2016;17:61–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Ibrahim SH, Gores GJ, Hirsova P, Kirby M, Miles L, Jaeschke A, et al. Mixed lineage kinase 3 deficient mice are protected against the high fat high carbohydrate diet-induced steatohepatitis. Liver Int. 2014;34:427–37.

    Article  CAS  PubMed  Google Scholar 

  10. Ibrahim SH, Hirsova P, Tomita K, Bronk SF, Werneburg NW, Harrison SA, et al. Mixed lineage kinase 3 mediates release of C-X-C motif ligand 10-bearing chemotactic extracellular vesicles from lipotoxic hepatocytes. Hepatology. 2016;63:731–44.

    Article  CAS  PubMed  Google Scholar 

  11. Tomita K, Kabashima A, Freeman BL, Bronk SF, Hirsova P, Ibrahim SH. Mixed Lineage Kinase 3 Mediates the Induction of CXCL10 by a STAT1-Dependent Mechanism During Hepatocyte Lipotoxicity. J Cell Biochem. 2017;118:3249–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Viswakarma N, Sondarva G, Principe DR, Nair RS, Kumar S, Singh SK, et al. Mixed Lineage Kinase 3 phosphorylates prolyl-isomerase PIN1 and potentiates GLI1 signaling in pancreatic cancer development. Cancer Lett. 2021;515:1–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Das S, Nair RS, Mishra R, Sondarva G, Viswakarma N, Abdelkarim H, et al. Mixed lineage kinase 3 promotes breast tumorigenesis via phosphorylation and activation of p21-activated kinase 1. Oncogene. 2019;38:3569–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schroyer AL, Stimes NW, Abi Saab WF, Chadee DN. MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells. Oncogene. 2018;37:1031���40.

    Article  CAS  PubMed  Google Scholar 

  15. Cedeno-Rosario L, Honda D, Sunderland AM, Lewandowski MD, Taylor WR, Chadee DN. Phosphorylation of mixed lineage kinase MLK3 by cyclin-dependent kinases CDK1 and CDK2 controls ovarian cancer cell division. J Biol Chem. 2022;298:102263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ramachandraiah K, Thylur Puttalingaiah R. The role of mixed lineage kinase 3 (MLK3) in cancers. Pharm Ther. 2022;238:108269.

    Article  CAS  Google Scholar 

  17. Kumar S, Singh SK, Viswakarma N, Sondarva G, Nair RS, Sethupathi P et al. Rationalized inhibition of mixed lineage kinase 3 and CD70 enhances life span and antitumor efficacy of CD8(+) T cells. J Immunother Cancer. 2020;8:e000494.

  18. Kumar S, Singh SK, Viswakarma N, Sondarva G, Nair RS, Sethupathi P, et al. Mixed lineage kinase 3 inhibition induces T cell activation and cytotoxicity. Proc Natl Acad Sci USA. 2020;117:7961–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tang G, Cho M, Wang X. OncoDB: an interactive online database for analysis of gene expression and viral infection in cancer. Nucleic Acids Res. 2022;50:D1334–D1339.

    Article  CAS  PubMed  Google Scholar 

  20. Cancer Genome Atlas Research Network, Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat Genet. 2013;45:1113–20.

    Article  PubMed Central  Google Scholar 

  21. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45:W98–W102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Matsumoto K, Huang J, Viswakarma N, Bai L, Jia Y, Zhu YT, et al. Transcription coactivator PBP/MED1-deficient hepatocytes are not susceptible to diethylnitrosamine-induced hepatocarcinogenesis in the mouse. Carcinogenesis. 2010;31:318–25.

    Article  CAS  PubMed  Google Scholar 

  23. Mishra P, Senthivinayagam S, Rangasamy V, Sondarva G, Rana B. Mixed lineage kinase-3/JNK1 axis promotes migration of human gastric cancer cells following gastrin stimulation. Mol Endocrinol. 2010;24:598–607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nair RS, Kumar S, Das S, Singh SK, Srivastava P, Sondarva G, et al. TrkA expression directs the anti-neoplastic activity of MLK3 inhibitors in triple-negative breast cancer. Oncogene. 2023;42:1132–43.

    Article  CAS  PubMed  Google Scholar 

  25. Vishnoi K, Ke R, Saini KS, Viswakarma N, Nair RS, Das S, et al. Berberine Represses beta-Catenin Translation Involving 4E-BPs in Hepatocellular Carcinoma Cells. Mol Pharm. 2021;99:1–16.

    Article  CAS  Google Scholar 

  26. Sharma M, Gadang V, Jaeschke A. Critical role for mixed-lineage kinase 3 in acetaminophen-induced hepatotoxicity. Mol Pharm. 2012;82:1001–7.

    Article  CAS  Google Scholar 

  27. Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007;213:374–83.

    Article  CAS  PubMed  Google Scholar 

  28. Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol. 2022;15:129.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  30. Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sureban SM, May R, Lightfoot SA, Hoskins AB, Lerner M, Brackett DJ, et al. DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism. Cancer Res. 2011;71:2328–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yuregir Y, Kacaroglu D, Yaylaci S. Regulation of Hepatocellular Carcinoma Epithelial-Mesenchymal Transition Mechanism and Targeted Therapeutic Approaches. Adv Exp Med Biol. 2024:1450:93–102.

  33. Sengez B, Carr BI, Alotaibi H. EMT and Inflammation: Crossroads in HCC. J Gastrointest Cancer. 2023;54:204–12.

    Article  CAS  PubMed  Google Scholar 

  34. Rana A, Gallo K, Godowski P, Hirai S, Ohno S, Zon L, et al. The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. J Biol Chem. 1996;271:19025–8.

    Article  CAS  PubMed  Google Scholar 

  35. Ke R, Vishnoi K, Viswakarma N, Santha S, Das S, Rana A, et al. Involvement of AMP-activated protein kinase and Death Receptor 5 in TRAIL-Berberine-induced apoptosis of cancer cells. Sci Rep. 2018;8:5521.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Kim E, Lisby A, Ma C, Lo N, Ehmer U, Hayer KE, et al. Promotion of growth factor signaling as a critical function of beta-catenin during HCC progression. Nat Commun. 2019;10:1909.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Liu X, Xu J, Rosenthal S, Zhang LJ, McCubbin R, Meshgin N, et al. Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution. Gastroenterology. 2020;158:1728–44.e1714.

    Article  CAS  PubMed  Google Scholar 

  38. Dropmann A, Dediulia T, Breitkopf-Heinlein K, Korhonen H, Janicot M, Weber SN, et al. TGF-beta1 and TGF-beta2 abundance in liver diseases of mice and men. Oncotarget. 2016;7:19499–518.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Dropmann A, Dooley S, Dewidar B, Hammad S, Dediulia T, Werle J, et al. TGF-beta2 silencing to target biliary-derived liver diseases. Gut. 2020;69:1677–90.

    Article  CAS  PubMed  Google Scholar 

  40. Kim KY, Kim BC, Xu Z, Kim SJ. Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in hepatoma cells. J Biol Chem. 2004;279:29478–84.

    Article  CAS  PubMed  Google Scholar 

  41. Sapkota GP. The TGFbeta-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1. Open Biol. 2013;3:130067.

    Article  PubMed  PubMed Central  Google Scholar 

  42. He X, Guo X, Zhang H, Kong X, Yang F, Zheng C. Mechanism of action and efficacy of LY2109761, a TGF-beta receptor inhibitor, targeting tumor microenvironment in liver cancer after TACE. Oncotarget. 2018;9:1130–42.

    Article  PubMed  Google Scholar 

  43. Dituri F, Mazzocca A, Fernando J, Peidro FJ, Papappicco P, Fabregat I, et al. Differential Inhibition of the TGF-beta Signaling Pathway in HCC Cells Using the Small Molecule Inhibitor LY2157299 and the D10 Monoclonal Antibody against TGF-beta Receptor Type II. PLoS One. 2013;8:e67109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Akil A, Endsley M, Shanmugam S, Saldarriaga O, Somasunderam A, Spratt H, et al. Fibrogenic Gene Expression in Hepatic Stellate Cells Induced by HCV and HIV Replication in a Three Cell Co-Culture Model System. Sci Rep. 2019;9:568.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, et al. Hepatocellular carcinoma. Nat Rev Dis Prim. 2021;7:6.

    Article  PubMed  Google Scholar 

  46. Zhang YE. Non-Smad Signaling Pathways of the TGF-beta Family. Cold Spring Harb Perspect Biol. 2017; 9:a022129.

  47. Xu P, Lin X, Feng XH. Posttranslational Regulation of Smads. Cold Spring Harb Perspect Biol. 2016;8:a022087.

  48. Sathyanarayana P, Barthwal MK, Kundu CN, Lane ME, Bergmann A, Tzivion G, et al. Activation of the Drosophila MLK by ceramide reveals TNF-alpha and ceramide as agonists of mammalian MLK3. Mol Cell. 2002;10:1527–33.

    Article  CAS  PubMed  Google Scholar 

  49. Korchnak AC, Zhan Y, Aguilar MT, Chadee DN. Cytokine-induced activation of mixed lineage kinase 3 requires TRAF2 and TRAF6. Cell Signal. 2009;21:1620–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Cuesta AM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sanchez A et al. New and Old Key Players in Liver Cancer. Int J Mol Sci. 2023;24:17152.

  51. Mu X, Lin S, Yang J, Chen C, Chen Y, Herzig MC, et al. TGF-beta signaling is often attenuated during hepatotumorigenesis, but is retained for the malignancy of hepatocellular carcinoma cells. PLoS One. 2013;8:e63436.

    Article  PubMed  PubMed Central  Google Scholar 

  52. David CJ, Massague J. Contextual determinants of TGFbeta action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19:419–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen J, Gingold JA, Su X. Immunomodulatory TGF-beta Signaling in Hepatocellular Carcinoma. Trends Mol Med. 2019;25:1010–23.

    Article  CAS  PubMed  Google Scholar 

  54. Coulouarn C, Factor VM, Thorgeirsson SS. Transforming growth factor-beta gene expression signature in mouse hepatocytes predicts clinical outcome in human cancer. Hepatology. 2008;47:2059–67.

    Article  CAS  PubMed  Google Scholar 

  55. Zeng X, Liao G, Li S, Liu H, Zhao X, Li S, et al. Eliminating METTL1-mediated accumulation of PMN-MDSCs prevents hepatocellular carcinoma recurrence after radiofrequency ablation. Hepatology. 2023;77:1122–38.

    Article  PubMed  Google Scholar 

  56. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.

    Article  CAS  PubMed  Google Scholar 

  57. Gregory PA, Bracken CP, Smith E, Bert AG, Wright JA, Roslan S, et al. An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Mol Biol Cell. 2011;22:1686–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li K, Guo J, Ming Y, Chen S, Zhang T, Ma H, et al. A circular RNA activated by TGFbeta promotes tumor metastasis through enhancing IGF2BP3-mediated PDPN mRNA stability. Nat Commun. 2023;14:6876.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Koetz-Ploch L, Hanniford D, Dolgalev I, Sokolova E, Zhong J, Diaz-Martinez M, et al. MicroRNA-125a promotes resistance to BRAF inhibitors through suppression of the intrinsic apoptotic pathway. Pigment Cell Melanoma Res. 2017;30:328–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Xu X, Tao Y, Niu Y, Wang Z, Zhang C, Yu Y, et al. miR-125a-5p inhibits tumorigenesis in hepatocellular carcinoma. Aging. 2019;11:7639–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zhang F, Zhu Y, Wu SH, Hou GD, Wu NX, Qian LR et al. MLK3 is a newly identified microRNA-520b target that regulates liver cancer cell migration. Plos One. 2020;15:e0230716.

  62. Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, et al. CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression. Cancer Res. 2018;78:4902–14.

    Article  CAS  PubMed  Google Scholar 

  63. Wallace MC, Friedman SL. Hepatic fibrosis and the microenvironment: fertile soil for hepatocellular carcinoma development. Gene Expr. 2014;16:77–84.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Zhang DY, Goossens N, Guo J, Tsai MC, Chou HI, Altunkaynak C, et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut. 2016;65:1754–64.

    Article  CAS  PubMed  Google Scholar 

  65. Myojin Y, Hikita H, Sugiyama M, Sasaki Y, Fukumoto K, Sakane S, et al. Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production. Gastroenterology. 2021;160:1741–54.e1716.

    Article  CAS  PubMed  Google Scholar 

  66. Liu WT, Jing YY, Yu GF, Chen H, Han ZP, Yu DD, et al. Hepatic stellate cell promoted hepatoma cell invasion via the HGF/c-Met signaling pathway regulated by p53. Cell Cycle. 2016;15:886–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Okrah K, Tarighat S, Liu B, Koeppen H, Wagle MC, Cheng G, et al. Transcriptomic analysis of hepatocellular carcinoma reveals molecular features of disease progression and tumor immune biology. NPJ. Precis Oncol. 2018;2:25.

    Article  CAS  Google Scholar 

  68. Senthivinayagam S, Mishra P, Paramasivam SK, Yallapragada S, Chatterjee M, Wong L, et al. Caspase-mediated Cleavage of {beta}-Catenin Precedes Drug-induced Apoptosis in Resistant Cancer Cells. J Biol Chem. 2009;284:13577–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sureau C, Moriarty AM, Thornton GB, Lanford RE. Production of infectious hepatitis delta virus in vitro and neutralization with antibodies directed against hepatitis B virus pre-S antigens. J Virol. 1992;66:1241–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Brancho D, Ventura JJ, Jaeschke A, Doran B, Flavell RA, Davis RJ. Role of MLK3 in the regulation of mitogen-activated protein kinase signaling cascades. Mol Cell Biol. 2005;25:3670–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30:923–30.

    Article  CAS  PubMed  Google Scholar 

  72. McCarthy DJ, Chen Y, Smyth GK. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 2012;40:4288–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26:139–40.

    Article  CAS  PubMed  Google Scholar 

  74. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B. 1995;57:289–300.

    Article  Google Scholar 

  75. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wickham H. ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2016.

  78. Vishnoi K, Ke R, Viswakarma N, Srivastava P, Kumar S, Das S, et al. Ets1 mediates sorafenib resistance by regulating mitochondrial ROS pathway in hepatocellular carcinoma. Cell Death Dis. 2022;13:581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Singh SK, Kumar S, Viswakarma N, Principe DR, Das S, Sondarva G, et al. MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3. Oncogene. 2021;40:6153–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Kumar S, Das S, Sun J, Huang Y, Singh SK, Srivastava P, et al. Mixed lineage kinase 3 and CD70 cooperation sensitize trastuzumab-resistant HER2(+) breast cancer by ceramide-loaded nanoparticles. Proc Natl Acad Sci USA. 2022;119:e2205454119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Institutes of Health grants CA219764 (to BR), CA216410 (to AR), and the Veterans Affairs Merit Award grants BX003296, BX005791 (to BR), BX004903 and BX004855 (to AR). The contents of this article are solely the responsibility of the authors and do not represent the views of the Department of Veterans Affairs or the United States Government.

Author information

Author notes

  1. Navin Viswakarma

    Present address: O2M Technologies, LLC, Chicago, IL, 60612, USA

Authors and Affiliations

  1. Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Rong Ke, Navin Viswakarma, Sunil Kumar Singh, Sandeep Kumar, Piush Srivastava, Kanchan Vishnoi, Tanushree Kashyap, Deepti Srivastava, Rakesh Sathish Nair, Ajay Rana & Basabi Rana

  2. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, 60607, USA

    Rong Ke

  3. Department of Pharmacology & Regenerative Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Mary Menhart & Xiaowei Wang

  4. University of Illinois Hospital and Health Sciences System Cancer Center, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Sandeep Kumar, Ajay Rana & Basabi Rana

  5. Research Informatics Core, University of Illinois at Chicago, Chicago, IL, 60612, USA

    Mark Maienschein-Cline

  6. Jesse Brown VA Medical Center, Chicago, IL, 60612, USA

    Ajay Rana & Basabi Rana

Authors
  1. Rong Ke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Navin Viswakarma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mary Menhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sunil Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandeep Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Piush Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kanchan Vishnoi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tanushree Kashyap
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Deepti Srivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rakesh Sathish Nair
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Mark Maienschein-Cline
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Xiaowei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ajay Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Basabi Rana
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: RK, NV, AR, BR. Methodology: RK, NV, MM, SKS, SK, PS, KV, TK, DS, RSN. Investigation: RK, NV, MM, SKS, SK, PS, KV, TK, DS, RSN. Visualization: RK, NV, SK, PS, KV, TK, DS. Supervision: MMC, XW, AR, BR. Writing—original draft: RK, BR. Writing—review & editing: MM, MMC, XW, AR, BR.

Corresponding author

Correspondence to Basabi Rana.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ke, R., Viswakarma, N., Menhart, M. et al. MLK3 promotes prooncogenic signaling in hepatocellular carcinoma via TGFβ pathway. Oncogene 43, 2307–2324 (2024). https://doi.org/10.1038/s41388-024-03055-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-024-03055-8

Search

Advanced search

Quick links