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:

T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1

Oncogene volume 41, pages 2225–2238 (2022)Cite this article

Subjects

Abstract

The effect of targeted therapy for metastatic hepatocellular carcinoma (HCC) is still unsatisfactory. Exploring the underlying mechanism of HCC metastasis is favorable to provide new therapeutic strategies. T-box (TBX) transcription factor family genes, which are crucial regulators in embryo and organ development, are vital for regulating tumor initiation, growth and metastasis. Here we explored the role of TBX19 in HCC metastasis, which is one of the most upregulated TBX family genes in human HCC tissues. TBX19 expression was markedly upregulated in HCC tissues and elevated TBX19 expression predicted poor prognosis. Overexpression of TBX19 enhanced HCC metastasis through upregulating epidermal growth factor receptor (EGFR) and Rac family small GTPase 1 (RAC1) expression. Downregulation of EGFR and RAC1 inhibited TBX19-mediated HCC metastasis, while upregulation of EGFR and RAC1 restored inhibition of HCC metastasis mediated by TBX19 knockdown. Furthermore, epidermal growth factor (EGF)/EGFR signaling upregulated TBX19 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor (NF)-kB axis. Besides, the combined application of EGFR inhibitor Erlotinib and RAC1 inhibitor NSC23766 markedly inhibited TBX19-mediated HCC metastasis. In HCC cohorts, TBX19 expression was positively associated with EGFR and RAC1 expression. Patients with positive coexpression of TBX19/EGFR or TBX19/RAC1 displayed the poorest prognosis. In conclusion, EGF/EGFR signaling upregulated TBX19 expression via ERK/NF-kB pathway and TBX19 fostered HCC metastasis by enhancing EGFR and RAC1 expression, which formed an EGF-TBX19-EGFR positive feedback loop. Targeting this signaling pathway may offer a potential therapeutic strategy to efficiently restrain TBX19-mediated HCC metastasis.

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: The elevated expression of TBX19 is related to poor prognosis in HCC patients and overexpression of TBX19 facilitates HCC metastasis.
Fig. 2: TBX19 fosters HCC metastasis by upregulating the expression of EGFR and RAC1.
Fig. 3: TBX19 expression is upregulated by EGF via the ERK/NF-κB pathway.
Fig. 4: TBX19 is crucial in EGF-induced HCC metastasis.
Fig. 5: TBX19 expression is positively related to EGFR and RAC1 levels in human HCC tissues.
Fig. 6: Combined treatment with EGFR and RAC1 inhibitor significantly alleviates TBX19-induced HCC metastasis.

Similar content being viewed by others

References

  1. Liu Z, Lin Y, Zhang J, Zhang Y, Li Y, Liu Z, et al. Molecular targeted and immune checkpoint therapy for advanced hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38:447.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zhu YJ, Zheng B, Wang HY, Chen L. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharm Sin. 2017;38:614–22.

    Article  CAS  Google Scholar 

  3. Gordan JD, Kennedy EB, Abou-Alfa GK, Beg MS, Brower ST, Gade TP, et al. Systemic therapy for advanced hepatocellular carcinoma: ASCO guideline. J Clin Oncol. 2020;38:4317–45.

    Article  CAS  Google Scholar 

  4. Finn RS, Zhu AX. Evolution of systemic therapy for hepatocellular carcinoma. Hepatology. 2021;73:150–7.

    Article  PubMed  Google Scholar 

  5. Papaioannou VE. The T-box gene family: emerging roles in development, stem cells and cancer. Development. 2014;141:3819–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chang F, Xing P, Song F, Du X, Wang G, Chen K, et al. The role of T-box genes in the tumorigenesis and progression of cancer. Oncol Lett. 2016;12:4305–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu X, Miao Z, Wang Z, Zhao T, Xu Y, Song Y, et al. TBX2 overexpression promotes proliferation and invasion through epithelial-mesenchymal transition and ERK signaling pathway. Exp Ther Med. 2019;17:723–9.

    CAS  PubMed  Google Scholar 

  8. Zhao S, Shen W, Yu J, Wang L. TBX21 predicts prognosis of patients and drives cancer stem cell maintenance via the TBX21-IL-4 pathway in lung adenocarcinoma. Stem Cell Res Ther. 2018;9:89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Roselli M, Fernando RI, Guadagni F, Spila A, Alessandroni J, Palmirotta R, et al. Brachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer. Clin Cancer Res. 2012;18:3868–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zong M, Meng M, Li L. Low expression of TBX4 predicts poor prognosis in patients with stage II pancreatic ductal adenocarcinoma. Int J Mol Sci. 2011;12:4953–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dong X, Song J, Hu J, Zheng C, Zhang X, Liu H. T-Box transcription factor 22 is an immune microenvironment-related biomarker associated with the BRAF (V600E) mutation in papillary thyroid carcinoma. Front Cell Dev Biol. 2020;8:590898.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Wang N, Li Y, Wei J, Pu J, Liu R, Yang Q, et al. TBX1 functions as a tumor suppressor in thyroid cancer through inhibiting the activities of the PI3K/AKT and MAPK/ERK pathways. Thyroid. 2019;29:378–94.

    Article  CAS  PubMed  Google Scholar 

  13. Cui J, Zhang Y, Ren X, Jin L, Zhang H. TBX1 functions as a tumor activator in prostate cancer by promoting ribosome RNA gene transcription. Front Oncol. 2020;10:616173.

    Article  PubMed  Google Scholar 

  14. Wansleben S, Peres J, Hare S, Goding CR, Prince S. T-box transcription factors in cancer biology. Biochim Biophys Acta. 2014;1846:380–91.

    CAS  PubMed  Google Scholar 

  15. Koinis F, Corn P, Parikh N, Song J, Vardaki I, Mourkioti I, et al. Resistance to MET/VEGFR2 inhibition by cabozantinib is mediated by YAP/TBX5-dependent induction of FGFR1 in castration-resistant prostate cancer. Cancers (Basel). 2020;12:244.

  16. Yu J, Ma X, Cheung KF, Li X, Tian L, Wang S, et al. Epigenetic inactivation of T-box transcription factor 5, a novel tumor suppressor gene, is associated with colon cancer. Oncogene. 2010;29:6464–74.

    Article  CAS  PubMed  Google Scholar 

  17. Abrahams A, Parker MI, Prince S. The T-box transcription factor Tbx2: its role in development and possible implication in cancer. IUBMB Life. 2010;62:92–102.

    CAS  PubMed  Google Scholar 

  18. Renard CA, Labalette C, Armengol C, Cougot D, Wei Y, Cairo S, et al. Tbx3 is a downstream target of the Wnt/beta-catenin pathway and a critical mediator of beta-catenin survival functions in liver cancer. Cancer Res. 2007;67:901–10.

    Article  CAS  PubMed  Google Scholar 

  19. Dong L, Dong Q, Chen Y, Li Y, Zhang B, Zhou F, et al. Novel HDAC5-interacting motifs of Tbx3 are essential for the suppression of E-cadherin expression and for the promotion of metastasis in hepatocellular carcinoma. Signal Transduct Target Ther. 2018;3:22.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liang B, Zhou Y, Qian M, Xu M, Wang J, Zhang Y, et al. TBX3 functions as a tumor suppressor downstream of activated CTNNB1 mutants during hepatocarcinogenesis. J Hepatol. 2021;75:120–31.

    Article  CAS  PubMed  Google Scholar 

  21. Liu J, Lin C, Gleiberman A, Ohgi KA, Herman T, Huang HP, et al. Tbx19, a tissue-selective regulator of POMC gene expression. Proc Natl Acad Sci USA. 2001;98:8674–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lamolet B, Pulichino AM, Lamonerie T, Gauthier Y, Brue T, Enjalbert A, et al. A pituitary cell-restricted T box factor, Tpit, activates POMC transcription in cooperation with Pitx homeoproteins. Cell. 2001;104:849–59.

    Article  CAS  PubMed  Google Scholar 

  23. Wilson V, Conlon FL. The T-box family. Genome Biol. 2002;3:REVIEWS3008.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ando J, Saito M, Imai JI, Ito E, Yanagisawa Y, Honma R, et al. TBX19 is overexpressed in colorectal cancer and associated with lymph node metastasis. Fukushima J Med Sci. 2017;63:141–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. London M, Gallo E. Epidermal growth factor receptor (EGFR) involvement in epithelial-derived cancers and its current antibody-based immunotherapies. Cell Biol Int. 2020;44:1267–82.

    Article  CAS  PubMed  Google Scholar 

  26. Lowery FJ, Yu D. Growth factor signaling in metastasis: current understanding and future opportunities. Cancer Metastasis Rev. 2012;31:479–91.

    Article  CAS  PubMed  Google Scholar 

  27. Hu W, Zheng S, Guo H, Dai B, Ni J, Shi Y, et al. PLAGL2-EGFR-HIF-1/2alpha signaling loop promotes HCC progression and erlotinib insensitivity. Hepatology. 2021;73:674–91.

    Article  CAS  PubMed  Google Scholar 

  28. Komposch K, Sibilia M. EGFR signaling in liver diseases. Int J Mol Sci. 2015;17:30.

  29. Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med. 2013;19:1389–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kang L, Zhang ZH, Zhao Y. SCAMP3 is regulated by miR-128-3p and promotes the metastasis of hepatocellular carcinoma cells through EGFR-MAPK p38 signaling pathway. Am J Transl Res. 2020;12:7870–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Feng X, Yao W, Zhang Z, Yuan F, Liang L, Zhou J, et al. T-box transcription factor Tbx3 contributes to human hepatocellular carcinoma cell migration and invasion by repressing E-cadherin expression. Oncol Res. 2018;26:959–66.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol. 2008;129:245–51.

    Article  PubMed  Google Scholar 

  33. Bayo J, Fiore EJ, Dominguez LM, Cantero MJ, Ciarlantini MS, Malvicini M, et al. Bioinformatic analysis of RHO family of GTPases identifies RAC1 pharmacological inhibition as a new therapeutic strategy for hepatocellular carcinoma. Gut. 2021;70:1362–74.

    Article  CAS  PubMed  Google Scholar 

  34. Furuse J. Growth factors as therapeutic targets in HCC. Crit Rev Oncol Hematol. 2008;67:8–15.

    Article  PubMed  Google Scholar 

  35. Liu S, Yu M, He Y, Xiao L, Wang F, Song C, et al. Melittin prevents liver cancer cell metastasis through inhibition of the Rac1-dependent pathway. Hepatology. 2008;47:1964–73.

    Article  CAS  PubMed  Google Scholar 

  36. He Q, Liu M, Huang W, Chen X, Zhang B, Zhang T, et al. IL-1beta-induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up-regulating programmed death ligand 1 and colony-stimulating factor 1. Hepatology. 2021;74:3174–93.

    Article  CAS  PubMed  Google Scholar 

  37. Chen J, Du F, Dang Y, Li X, Qian M, Feng W, et al. Fibroblast growth factor 19-mediated up-regulation of SYR-related high-mobility group box 18 promotes hepatocellular carcinoma metastasis by transactivating fibroblast growth factor receptor 4 and Fms-related tyrosine kinase 4. Hepatology. 2020;71:1712–31.

  38. He Q, Lin Z, Wang Z, Huang W, Tian D, Liu M, et al. SIX4 promotes hepatocellular carcinoma metastasis through upregulating YAP1 and c-MET. Oncogene. 2020;39:7279–95.

    Article  PubMed  Google Scholar 

  39. Yoneda N, Sato Y, Kitao A, Ikeda H, Sawada-Kitamura S, Miyakoshi M, et al. Epidermal growth factor induces cytokeratin 19 expression accompanied by increased growth abilities in human hepatocellular carcinoma. Lab Invest. 2011;91:262–72.

    Article  CAS  PubMed  Google Scholar 

  40. Liu Z, Chen D, Ning F, Du J, Wang H. EGF is highly expressed in hepatocellular carcinoma (HCC) and promotes motility of HCC cells via fibronectin. J Cell Biochem. 2018;119:4170–83.

    Article  CAS  PubMed  Google Scholar 

  41. Xu MJ, Johnson DE, Grandis JR. EGFR-targeted therapies in the post-genomic era. Cancer Metastasis Rev. 2017;36:463–73.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci USA. 2004;101:7618–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tang M, Yang M, Wu G, Mo S, Wu X, Zhang S, et al. Epigenetic induction of mitochondrial fission is required for maintenance of liver cancer-initiating cells. Cancer Res. 2021;81:3835–48.

    Article  CAS  PubMed  Google Scholar 

  44. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science. 2011;331:1559–64.

    Article  CAS  PubMed  Google Scholar 

  45. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12:3–20.

    Article  PubMed  Google Scholar 

  46. Zhangyuan G, Wang F, Zhang H, Jiang R, Tao X, Yu D, et al. VersicanV1 promotes proliferation and metastasis of hepatocellular carcinoma through the activation of EGFR-PI3K-AKT pathway. Oncogene. 2020;39:1213–30.

    Article  CAS  PubMed  Google Scholar 

  47. Zhou Q, Huang T, Jiang Z, Ge C, Chen X, Zhang L, et al. Upregulation of SNX5 predicts poor prognosis and promotes hepatocellular carcinoma progression by modulating the EGFR-ERK1/2 signaling pathway. Oncogene. 2020;39:2140–55.

    Article  CAS  PubMed  Google Scholar 

  48. Zhang J, Zong Y, Xu GZ, Xing K. Erlotinib for advanced hepatocellular carcinoma. A systematic review of phase II/III clinical trials. Saudi Med J. 2016;37:1184–90.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Liang J, Oyang L, Rao S, Han Y, Luo X, Yi P, et al. Rac1, a potential target for tumor therapy. Front Oncol. 2021;11:674426.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Cao X, Zhang L, Shi Y, Sun Y, Dai S, Guo C, et al. Human tumor necrosis factor (TNF)-alpha-induced protein 8-like 2 suppresses hepatocellular carcinoma metastasis through inhibiting Rac1. Mol Cancer. 2013;12:149.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Bid HK, Roberts RD, Manchanda PK, Houghton PJ. RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther. 2013;12:1925–34.

    Article  CAS  PubMed  Google Scholar 

  52. Zhu G, Fan Z, Ding M, Zhang H, Mu L, Ding Y, et al. An EGFR/PI3K/AKT axis promotes accumulation of the Rac1-GEF Tiam1 that is critical in EGFR-driven tumorigenesis. Oncogene. 2015;34:5971–82.

    Article  CAS  PubMed  Google Scholar 

  53. Kaneto N, Yokoyama S, Hayakawa Y, Kato S, Sakurai H, Saiki I. RAC1 inhibition as a therapeutic target for gefitinib-resistant non-small-cell lung cancer. Cancer Sci. 2014;105:788–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cannon AC, Uribe-Alvarez C, Chernoff J. RAC1 as a therapeutic target in malignant melanoma. Trends Cancer. 2020;6:478–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Huang P, Xu X, Wang L, Zhu B, Wang X, Xia J. The role of EGF-EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J Cell Mol Med. 2014;18:218–30.

    Article  CAS  PubMed  Google Scholar 

  56. Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;110:1059–67.

    Article  CAS  PubMed  Google Scholar 

  57. Karachaliou N, Codony-Servat J, Bracht JWP, Ito M, Filipska M, Pedraz C, et al. Characterising acquired resistance to erlotinib in non-small cell lung cancer patients. Expert Rev Respir Med. 2019;13:1019–28.

    Article  CAS  PubMed  Google Scholar 

  58. Gastonguay A, Berg T, Hauser AD, Schuld N, Lorimer E, Williams CL. The role of Rac1 in the regulation of NF-kappaB activity, cell proliferation, and cell migration in non-small cell lung carcinoma. Cancer Biol Ther. 2012;13:647–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zhou K, Rao J, Zhou ZH, Yao XH, Wu F, Yang J, et al. RAC1-GTP promotes epithelial-mesenchymal transition and invasion of colorectal cancer by activation of STAT3. Lab Invest. 2018;98:989–98.

    Article  CAS  PubMed  Google Scholar 

  60. Gudino V, Pohl SO, Billard CV, Cammareri P, Bolado A, Aitken S, et al. RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways. Nat Commun. 2021;12:2335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Li D, Ding X, Xie M, Huang Z, Han P, Tian D, et al. CAMSAP2-mediated noncentrosomal microtubule acetylation drives hepatocellular carcinoma metastasis. Theranostics. 2020;10:3749–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Research was supported by grants from the National Natural Science Foundation of China No. 81871911 (WH), No. 81972237 (LX), No. 81772623 (LX), and National Key Research and Development Program of China 2018YFC1312103 (LX).

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Xiaoyu Ji, Meng Xie, Tongyue Zhang, Xiangyuan Luo, Danfei Liu, Yangyang Feng, Yijun Wang, Mengyu Sun, Congxin Li & Limin Xia

  2. Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, 430030, Hubei, China

    Xiaoping Chen, Bixiang Zhang & Wenjie Huang

Authors
  1. Xiaoyu Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bixiang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Meng Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tongyue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiangyuan Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Danfei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yangyang Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yijun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Mengyu Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Congxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Wenjie Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Limin Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

XJ performed the experiments. XC and BZ assisted in experiment design. MX, TZ, XL, DL, and YF assisted in animal experiments and analyzing data. YW, MS, and CL assisted in collecting tissue samples. LX, WH, and XJ designed the studies and wrote the paper.

Corresponding authors

Correspondence to Wenjie Huang or Limin Xia.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ji, X., Chen, X., Zhang, B. et al. T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1. Oncogene 41, 2225–2238 (2022). https://doi.org/10.1038/s41388-022-02249-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02249-2

This article is cited by

Search

Advanced search

Quick links