Skip to main content

Advertisement

SpringerLink
Log in

Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background and Aims

Colitis-associated cancer (CAC) is one of the most serious complications in patients with inflammatory bowel disease. Sphingosine kinase 1 (Sphk1) is a key enzyme in the sphingolipid pathway and has oncogene potential for inducing both initiation and progression of tumors. The aim of this work is to characterize the role of epithelial Sphk1 in mouse colitis and CAC models.

Methods

We investigated the roles of Sphk1 in CAC by conditional deletion of Sphk1 in intestinal epithelial cells (IECs).

Results

CAC was induced in both Sphk1ΔIEC/ApcMin/+ and Sphk1IEC/ApcMin/+ mice by administration of 2% dextran sodium sulfate (DSS) for 7 days. Genetic deletion of Sphk1 significantly reduced the number and size of tumors in ApcMin/+ mice. Histologic grade was more severe in Sphk1ΔIEC/ApcMin/+ mice compared with Sphk1IEC/ApcMin/+ mice (invasive carcinoma, 71% versus 13%, p < 0.05). Deletion of Sphk1 decreased mucosal proliferation and inhibited STAT3 activation and genetic expression of cyclin D1 and cMyc in tumor cells. Conditional deletion of Sphk1 using CRISPR-Cas9 in HCT 116 cells inhibited interleukin (IL)-6-mediated STAT3 activation.

Conclusions

Epithelial conditional deletion of Sphk1 inhibits CAC in ApcMin/+-DSS models in mice by inhibiting STAT3 activation and its target signaling pathways.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–867.

    Article  CAS  Google Scholar 

  2. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357:539–545.

    Article  CAS  Google Scholar 

  3. Bernstein CN, Blanchard JF, Kliewer E, et al. Cancer risk in patients with inflammatory bowel disease—a population-based study. Cancer. 2001;91:854–862.

    Article  CAS  Google Scholar 

  4. Munkholm P. Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther. 2003;18:1–5.

    Article  Google Scholar 

  5. Ng WK, Wong SH, Ng SC. Changing epidemiological trends of inflammatory bowel disease in Asia. Intest Res. 2016;14:111–119.

    Article  Google Scholar 

  6. Le Stunff H, Milstien S, Spiegel S. Generation and metabolism of bioactive sphingosine-1-phosphate. J Cell Biochem. 2004;92:882–899.

    Article  Google Scholar 

  7. Hait NC, Maiti A. The role of sphingosine-1-phosphate and ceramide-1-phosphate in inflammation and cancer. Mediat Inflamm. 2017;2017:4806541.

    Article  Google Scholar 

  8. Liu SQ, Xu CY, Wu WH, et al. Sphingosine kinase 1 promotes the metastasis of colorectal cancer by inducing the epithelial–mesenchymal transition mediated by the FAK/AKT/MMPs axis. Int J Oncol. 2019;54:41–52.

    CAS  PubMed  Google Scholar 

  9. Li W, Yu CP, Xia JT, et al. Sphingosine kinase 1 is associated with gastric cancer progression and poor survival of patients. Clin Cancer Res. 2009;15:1393–1399.

    Article  CAS  Google Scholar 

  10. Liu SQ, Su YJ, Qin MB, et al. Sphingosine kinase 1 promotes tumor progression and confers malignancy phenotypes of colon cancer by regulating the focal adhesion kinase pathway and adhesion molecules. Int J Oncol. 2013;42:617–626.

    Article  CAS  Google Scholar 

  11. Dirisina R, Katzman RB, Goretsky T, et al. p53 and PUMA independently regulate apoptosis of intestinal epithelial cells in patients and mice with colitis. Gastroenterology. 2011;141:1036–1045.

    Article  CAS  Google Scholar 

  12. Lee SD, Choe JW, Lee BJ, et al. Butein effects in colitis and interleukin-6/signal transducer and activator of transcription 3 expression. World J Gastroenterol. 2015;21:465.

    Article  Google Scholar 

  13. Tanaka T, Kohno H, Suzuki R, et al. Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. J Cancer. 2006;118:25–34.

    CAS  Google Scholar 

  14. Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell. 2009;15:91–102.

    Article  CAS  Google Scholar 

  15. Pulkoski-Gross MJ, Obeid LM. Molecular mechanisms of regulation of sphingosine kinase 1. Biochim Biophys Acta Mol Cell Biol Lipids. 2018;1863:1413–1422.

    Article  CAS  Google Scholar 

  16. Vadas M, Xia P, McCaughan G, et al. The role of sphingosine kinase 1 in cancer: oncogene or non-oncogene addiction? Biochim Biophys Acta. 2008;1781:442–447.

    Article  CAS  Google Scholar 

  17. Nemoto S, Nakamura M, Osawa Y, et al. Sphingosine kinase isoforms regulate oxaliplatin sensitivity of human colon cancer cells through ceramide accumulation and Akt activation. J Biol Chem. 2009;284:10422–10432.

    Article  CAS  Google Scholar 

  18. Liu SQ, Huang JA, Qin MB, et al. Sphingosine kinase 1 enhances colon cancer cell proliferation and invasion by upregulating the production of MMP-2/9 and uPA via MAPK pathways. Int J Colorectal Dis. 2012;27:1569–1578.

    Article  Google Scholar 

  19. Luo C, Zhang H. The role of proinflammatory pathways in the pathogenesis of colitis-associated colorectal cancer. Mediat Inflamm. 2017;2017:5126048.

    Article  Google Scholar 

  20. Grivennikov SI. Inflammation and colorectal cancer: colitis-associated neoplasia. Semin Immunopathol. 2013;35:229–244.

    Article  CAS  Google Scholar 

  21. Shafik NM, Gaber RA, Mohamed DA, et al. Hesperidin modulates dextran sulfate sodium-induced ulcerative colitis in rats: targeting sphingosine kinase-1- sphingosine 1 phosphate signaling pathway, mitochondrial biogenesis, inflammation, and apoptosis. J Biochem Mol Toxicol. 2019;33:e22312.

    Article  Google Scholar 

  22. Xi M, Ge J, Wang X, et al. Development of hydroxy-based sphingosine kinase inhibitors and anti-inflammation in dextran sodium sulfate induced colitis in mice. Bioorg Med Chem. 2016;24:3218–3230.

    Article  CAS  Google Scholar 

  23. Pulkoski-Gross MJ, Uys JD, Orr-Gandy KA, et al. Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis. Prostaglandins Other Lipid Mediat. 2017;130:47–56.

    Article  CAS  Google Scholar 

  24. Snider AJ, Kawamori T, Bradshaw SG, et al. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis. FASEB J. 2009;23:143–152.

    Article  CAS  Google Scholar 

  25. Yuza K, Nagahashi M, Shimada Y, et al. Upregulation of phosphorylated sphingosine kinase 1 expression in colitis-associated cancer. J Surg Res. 2018;231:323–330.

    Article  CAS  Google Scholar 

  26. Liang J, Nagahashi M, Kim EY, et al. Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer. Cancer Cell. 2013;23:107–120.

    Article  CAS  Google Scholar 

  27. Corvinus FM, Orth C, Moriggl R, et al. Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia. 2005;7:545–555.

    Article  CAS  Google Scholar 

  28. Musteanu M, Blaas L, Mair M, et al. Stat3 is a negative regulator of intestinal tumor progression in Apc(Min) mice. Gastroenterology. 2010;138:1003-U257.

    Article  Google Scholar 

  29. Han J, Theiss AL. Stat3: friend or foe in colitis and colitis-associated cancer? Inflamm Bowel Dis. 2014;20:2405–2411.

    Article  Google Scholar 

  30. Sugimoto K. Role of STAT3 in inflammatory bowel disease. World J Gastroenterol. 2008;14:5110–5114.

    Article  CAS  Google Scholar 

  31. Li W, Lee MR, Kim T, et al. Activated STAT3 may participate in tumor progression through increasing CD133/survivin expression in early stage of colon cancer. Biochem Biophys Res Commun. 2018;497:354–361.

    Article  CAS  Google Scholar 

  32. Mitsuyama K, Matsumoto S, Masuda J, et al. Therapeutic strategies for targeting the IL-6/STAT3 cytokine signaling pathway in inflammatory bowel disease. Anticancer Res. 2007;27:3749–3756.

    CAS  PubMed  Google Scholar 

  33. Kusaba T, Nakayama T, Yamazumi K, et al. Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep. 2006;15:1445–1451.

    CAS  PubMed  Google Scholar 

  34. Wang Y, Shen YC, Wang SN, et al. The role of STAT3 in leading the crosstalk between human cancers and the immune system. Cancer Lett. 2018;415:117–128.

    Article  CAS  Google Scholar 

  35. Grivennikov S, Karin E, Terzic J, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–113.

    Article  CAS  Google Scholar 

  36. Fukuda T, Naganuma M, Kanai T. Current new challenges in the management of ulcerative colitis. Intest Res. 2019;17:36–44.

    Article  Google Scholar 

  37. Lee SH, Kwon JE, Cho ML. Immunological pathogenesis of inflammatory bowel disease. Intest Res. 2018;16:26–42.

    Article  Google Scholar 

Download references

Acknowledgments

This work is supported by grants from the National Research Foundation of Korea (no. NRF-2011-0014256) and by experimental techniques from the Core Laboratory for Convergent Translational Research of Korea University College of Medicine (grant no. K1421417).

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Korea University Guro Hospital, College of Medicine, Korea University, 80, Guro-dong, Guro-gu, Seoul, Korea

    Seung Bin Park, Byung-il Choi, Beom Jae Lee, Nam Joo Kim, Yoon A. Jeong, Moon Kyung Joo, Hyo Jung Kim, Jong-Jae Park & Jae Seon Kim

  2. College of Pharmacy, Chungbuk National University, Cheongju, Korea

    Yoon-Seok Noh

  3. Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

    Hyun Joo Lee

Authors
  1. Seung Bin Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byung-il Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Beom Jae Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nam Joo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoon A. Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Moon Kyung Joo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hyo Jung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jong-Jae Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jae Seon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yoon-Seok Noh
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hyun Joo Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CBI and PSB contributed equally to this work. Conceptualization: LBJ. Formal analysis: KNJ, PSB, CBI, JYA, LHJ. Investigation: KNJ, PSB, CBI, JYA. Project administration: NYS. Supervision: LBJ. Visualization: CBI, JYA, KNJ. Writing—original draft: PSB, CBI, LBJ. Writing—review: PJJ, JMK, KJS, KHS. Writing—editing: LBJ, CBI.

Corresponding author

Correspondence to Beom Jae Lee.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 13 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Park, S.B., Choi, Bi., Lee, B.J. et al. Intestinal Epithelial Deletion of Sphk1 Prevents Colitis-Associated Cancer Development by Inhibition of Epithelial STAT3 Activation. Dig Dis Sci 65, 2284–2293 (2020). https://doi.org/10.1007/s10620-019-05971-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05971-2

Keywords

Search

Navigation