Skip to main content
Log in

LncRNA H19 Participates in Leukemia Inhibitory Factor Mediated Stemness Promotion in Colorectal Cancer Cells

  • Original Article
  • Published:
Biochemical Genetics Aims and scope Submit manuscript

Abstract

Colorectal cancer (CRC) is a common human malignancy and the third leading cause of cancer-related death worldwide. Cancer stem cells (CSCs) were considered to play important roles in the genesis and development of many tumors. In recent years, it has been observed that leukemia inhibitory factor (LIF) might be involved in the regulation of stemness in cancer cells. In this study, we observed that LIF could increase the spheroid formation and stemness marker expression (inculding Nanog and SOX2) in CRC cell lines, such as HCT116 and Caco2 cells. Meanwhile, we also observed that LIF could upregulate LncRNA H19 expression via PI3K/AKT pathway. Knockdown of the expression of LncRNA H19 could decrease the spheroid formation and SOX2 expression in LIF-treated HCT116 and Caco2 cells, and thereby LncRNA H19 knockdown could compensate for the stemness enhancement effects induced by LIF. Our results indicated that LncRNA H19 might participate in the stemness promotion of LIF in CRC cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The TCGA repository (https://portal.gdc.cancer.gov/projects/TCGA) was utilized, under the accession code: Colon adenocarcinoma (COAD). The survival analysis was performed at the website (http://www.oncolnc.org). The method is described in the section of material and method.

References

  • Ahmed D, Eide PW, Eilertsen IA et al (2013) Epigenetic and genetic features of 24 colon cancer cell lines. Oncogenesis 2:e71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Biller LH, Schrag D (2021) Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 325:669–685

    Article  CAS  PubMed  Google Scholar 

  • Borazanci E, Schram AM, Garralda E et al (2022) Phase I, first-in-human study of MSC-1 (AZD0171), a humanized anti-leukemia inhibitory factor monoclonal antibody, for advanced solid tumors. ESMO Open 7:100530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bressy C, Lac S, Nigri J et al (2018) LIF drives neural remodeling in pancreatic cancer and offers a new candidate biomarker. Can Res 78:909–921

    Article  CAS  Google Scholar 

  • Ding D, Li C, Zhao T et al (2018) LncRNA H19/miR-29b-3p/PGRN axis promoted epithelial-mesenchymal transition of colorectal cancer cells by acting on Wnt signaling. Mol Cells 41:423–435

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fidler MM, Bray F (2018) Global cancer inequalities. Front Oncol 8:293

    Article  PubMed  PubMed Central  Google Scholar 

  • Fumagalli A, Oost KC, Kester L et al (2020) Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 26:569–578

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghanei Z, Mehri N, Jamshidizad A, Joupari MD, Shamsara M (2020) Immunization against leukemia inhibitory factor and its receptor suppresses tumor formation of breast cancer initiating cells in BALB/c mouse. Sci Rep 10:11465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jorgensen MM, de la Puente P (2022) Leukemia inhibitory factor: an important cytokine in pathologies and cancer. Biomolecules 12:217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li CY, Li BX, Liang Y et al (2009) Higher percentage of CD133+ cells is associated with poor prognosis in colon carcinoma patients with stage IIIB. J Transl Med 7:56

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu YN, Niu S, Chen WY et al (2019) Leukemia inhibitory factor promotes castration-resistant prostate cancer and neuroendocrine differentiation by activated ZBTB46. Clin Cancer Res 25:4128–4140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma YS, Li W, Liu Y et al (2020) Targeting colorectal cancer stem cells as an effective treatment for colorectal cancer. Technol Cancer Res Treat 19:1533033819892261

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McLean K, Tan L, Bolland DE et al (2019) Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth. Oncogene 38:1576–1584

    Article  CAS  PubMed  Google Scholar 

  • Medema JP (2017) Targeting the colorectal cancer stem cell. N Engl J Med 377:888–890

    Article  PubMed  Google Scholar 

  • Munro MJ, Wickremesekera SK, Peng L et al (2018) Cancer stem cells in colorectal cancer: a review. J Clin Pathol 71:110–116

    Article  CAS  PubMed  Google Scholar 

  • Nicola NA, Babon JJ (2015) Leukemia inhibitory factor (LIF). Cytokine Growth Factor Rev 26:533–544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Connor ML, Xiang D, Shigdar S et al (2014) Cancer stem cells: a contentious hypothesis now moving forward. Cancer Lett 344:180–187

    Article  CAS  PubMed  Google Scholar 

  • Ohtsuka M, Ling H, Ivan C et al (2016) H19 noncoding RNA, an independent prognostic factor, regulates essential Rb-E2F and CDK8-beta-catenin signaling in colorectal cancer. EBioMedicine 13:113–124

    Article  PubMed  PubMed Central  Google Scholar 

  • Pascual G, Avgustinova A, Mejetta S et al (2017) Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 541:41–45

    Article  CAS  PubMed  Google Scholar 

  • Pastrana E, Silva-Vargas V, Doetsch F (2011) Eyes wide open: a critical review of sphere-formation as an assay for stem cells. Cell Stem Cell 8:486–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peng F, Li TT, Wang KL et al (2017) H19/let-7/LIN28 reciprocal negative regulatory circuit promotes breast cancer stem cell maintenance. Cell Death Dis 8:e2569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raveh E, Matouk IJ, Gilon M, Hochberg A (2015) The H19 Long non-coding RNA in cancer initiation, progression and metastasis—a proposed unifying theory. Mol Cancer 14:184

    Article  PubMed  PubMed Central  Google Scholar 

  • Ren J, Ding L, Zhang D et al (2018) Carcinoma-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer by transferring exosomal lncRNA H19. Theranostics 8:3932–3948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ruella MX, Barrett DM, Fraietta JA et al (2018) Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat Med 24:1499–1503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakariassen PO, Immervoll H, Chekenya M (2007) Cancer stem cells as mediators of treatment resistance in brain tumors: status and controversies. Neoplasia 9:882–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sasaki N, Hirano K, Shichi Y et al (2022) Gp130-mediated STAT3 activation contributes to the aggressiveness of pancreatic cancer through H19 long non-coding RNA expression. Cancers 14:2055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi Y, Gao W, Lytle NK et al (2019) Targeting LIF-mediated paracrine interaction for pancreatic cancer therapy and monitoring. Nature 569:131–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics. CA: A Cancer J Clin 72:7–33

    Google Scholar 

  • Statello L, Guo CJ, Chen LL, Huarte M (2021) Gene regulation by long non-coding RNAs and its biological functions. Nat Rev Mol Cell Biol 22:96–118

    Article  CAS  PubMed  Google Scholar 

  • Sung H, Ferlay J, Siegel RL 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

    Google Scholar 

  • Takeda K, Mizushima T, Yokoyama Y et al (2018) Sox2 is associated with cancer stem-like properties in colorectal cancer. Sci Rep 8:17639

    Article  PubMed  PubMed Central  Google Scholar 

  • Viswanadhapalli S, Dileep KV, Zhang KYJ et al (2021) Targeting LIF/LIFR signaling in cancer. Genes Dis 9:973–980

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang YJ, Bailey JM, Rovira M, Leach SD (2013) Sphere-forming assays for assessment of benign and malignant pancreatic stem cells. Methods Mol Biol 980:281–290

    Article  CAS  PubMed  Google Scholar 

  • Xi X, Li X, Wu F et al (2017) Expression, purification and characterization of active untagged recombinant human leukemia inhibitory factor from E. coli. Protein Expr Purif 134:139–146

    Article  CAS  PubMed  Google Scholar 

  • Yang J, Liao D, Chen C et al (2013) Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells 31:248–258

    Article  CAS  PubMed  Google Scholar 

  • Yang W, Li X, Qi S et al (2017) lncRNA H19 is involved in TGF-beta1-induced epithelial to mesenchymal transition in bovine epithelial cells through PI3K/AKT signaling pathway. PeerJ 5:e3950

    Article  PubMed  PubMed Central  Google Scholar 

  • Yu H, Yue X, Zhao Y et al (2014) LIF negatively regulates tumour-suppressor p53 through Stat3/ID1/MDM2 in colorectal cancers. Nat Commun 5:5218–5229

    Article  CAS  PubMed  Google Scholar 

  • Yue X, Wu F, Wang J et al (2020) EC330, a small-molecule compound, is a potential novel inhibitor of LIF signaling. J Mol Cell Biol 12:477–480

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhang C, Liu J, Wang J, Hu W, Feng Z (2021) The emerging role of leukemia inhibitory factor in cancer and therapy. Pharmacol Ther 221:107754

    Article  CAS  PubMed  Google Scholar 

  • Zhou J, Xu J, Zhang L et al (2019) Combined single-cell profiling of lncRNAs and functional screening reveals that H19 is pivotal for embryonic hematopoietic stem cell development. Cell Stem Cell 24(285–298):e285

    Article  Google Scholar 

  • Zhou C, Fan N, Liu F et al (2020) Linking cancer stem cell plasticity to therapeutic resistance-mechanism and novel therapeutic strategies in esophageal cancer. Cells 9:1481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by grants from the National Natural Science Foundation of China (81772649). The Foundation of Health Commission of Hubei Province (WJ2021M057). The Scientific and Technological Project of Shiyan City, Hubei Province (2021K62). Innovative Research Program for Graduated of Hubei University of Medicine (YC2022010, YC2023017). National Training Program of Innovation and Entrepreneurship for Undergraduates (202210929003, 202210929006). The funders had no role in study design, data collection and analysis, the decision to publish, or the preparation of this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Conceived and designed the experiments: XX BD. Performed the experiments: MZ, RY, YL, QL, SL. Analyzed the data: XG, YG, BD. Contributed reagents/materials/analysis tools: YZ, GL. Wrote the paper: XX BD. All authors commented and approved the final version.

Corresponding authors

Correspondence to Xueyan Xi or Boyu Du.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Research Involving Human and Animal Rights

Human samples and animal experiments are not used in this study.

Consent for Publication

Not applicable.

Additional information

Publisher's Note

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

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

Zhu, M., Yu, R., Liu, Y. et al. LncRNA H19 Participates in Leukemia Inhibitory Factor Mediated Stemness Promotion in Colorectal Cancer Cells. Biochem Genet (2024). https://doi.org/10.1007/s10528-023-10627-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10528-023-10627-y

Keywords

Navigation