Abstract

  Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed primary liver cancer and is refractory to most of the chemotherapeutic drugs available. Multiple signalling pathways are deregulated in HCC, and two important developmental signalling pathways which are deregulated in HCC are Wnt and Hh signalling pathways. In various cancer models both pathways have been found to interact with each other at different levels and this interaction is known to play important role in the pathophysiology of those cancers like pancreatic cancer, colon cancer, and basal cell carcinoma. Previously we have shown that the Wnt and Hh pathways correlate positively and play an important role in the progression of hepatocarcinogenesis in rodent model. Our previously published data suggested that the investigation of cross-talk between these two pathways holds potential for identification of better HCC treatment strategies. In the present study we utilized pharmacological inhibitors of Wnt and Hh signalling pathways to unravel the functional interaction between these two pathways. We studied the impact of inhibition or up-regulation of Wnt signalling pathway on Hh signalling pathway outcome. We also investigated the chemo-preventive action of Sulindac Sulphide, a Wnt/b-catenin pathway inhibitor on tumorigenesis in animal model of hepatocarcinogenesis. Our study elaborated the nature of cross-talk between these two well known aberrant signalling pathways in HCC which would further pave the way for development of better combination therapy approach for targeting these two pathways in HCC.

Keywords: Hepatocellular Carcinoma; Sulindac Sulphide; KAAD-Cyclopamine; Wnt/β-catenin; Hh/Gli1

References

1. Kumari R., et al. “Hepatocellular carcinoma treatment: hurdles, advances and prospects”. Hepatology Oncology 5.2 (2018): HEP08.
2. Kumari R., et al. “Mitomycin C induces bystander killing in homogeneous and heterogeneous hepatoma cellular models”. Molecular Cancer 8 (2009): 87.
3. Jiapei Guo., et al. “Mechanisms of resistance to chemotherapy and radiotherapy in hepatocellular carcinoma”. Translational Cancer Research 7.3 (2018): 765-781.
4. Ghouri YA., et al. “Review of hepatocellular carcinoma: Epidemiology, etiology, and carcinogenesis”. Journal of Carcinogenesis 16 (2017): 1.
5. M Setshedi., et al. “Molecular and cellular oncogenic mechanisms in hepatocellular carcinoma’. South African Medical Journal 108 (2018): S41-S46.
6. Tripathy A., et al. “The molecular connection of histopathological heterogeneity in hepatocellular carcinoma: A role of Wnt and Hedgehog signaling pathways”. PLoS One 13.12 (2018): e0208194.
7. Ingham PW and McMahon AP. “Hedgehog signaling in animal development: paradigms and principles”. Genes and Development 15 (2001): 3059-3087.
8. Pasca di Magliano M., et al. “Common activation of canonical Wnt signaling in pancreatic adenocarcinoma”. PLoS One 2.11 (2007): e1155.
9. Song L., et al. “Crosstalk between Wnt/β-catenin and Hedgehog/Gli signaling pathways in colon cancer and implications for therapy”. Cancer Biology Therapy 16.1 (2015): 1-7.
10. Noubissi FK., et al. “Cross-Talk between Wnt and Hh Signaling Pathways in the Pathology of Basal Cell Carcinoma”. International Journal of Environmental Research and Public Health 15.7 (2018): 1442.
11. Giakoustidis A., et al. “Molecular signalling in hepatocellular carcinoma: Role of and crosstalk among WNT/ß-catenin, Sonic Hedgehog, Notch and Dickkopf-1”. Canadian Journal of Gastroenterology and Hepatology 29.4 (2015): 209-217.
12. Goldsberry WN., et al. “A Review of the Role of Wnt in Cancer Immunomodulation”. Cancers (Basel) 11.6 (2019): 771.
13. Della Corte CM., et al. “Implication of the Hedgehog pathway in hepatocellular carcinoma”. World Journal of Gastroenterology 23.24 (2017): 4330-4340.
14. Li X., et al. “Sulindac sulfide inhibits colon cancer cell growth and downregulates specificity protein transcription factors”. BMC Cancer 15 (2015): 974.
15. Jason D., et al. “A Novel Sulindac Derivative that Potently Suppresses Colon Tumor Cell Growth by Inhibiting cGMP Phosphodiesterase and β-Catenin Transcriptional Activity”. Cancer Preventive Research (2012): 822-833. 
16. Lee HJ., et al. “Sulindac inhibits canonical Wnt signaling by blocking the PDZ domain of the protein Dishevelled”. Angewandte Chemie International Edition 48.35 (2009): 6448-6452.
17. Chen JK., et al. “Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened”. Genes and Development 16.21 (2002): 2743-2748. 
18. Sari IN., et al. “Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells”. Cells 7.11 (2018): 208.
19. Xie H., et al. “Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer”. Cells 8.5 (2019): 394.
20. Stambolic V., et al. “Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells”. Current Biology 6 (1996): 1664-1669.
21. O'Brien WT and Klein PS. “Validating GSK3 as an in vivo target of lithium action”. Biochemical Society Transactions 37 (2009): 1133-1138.
22. Derksen PW., et al. “Illegitimate WNT signaling promotes proliferation of multiple myeloma cells”. Proceedings of the National Academy of Sciences of the United States of America 101.16 (2004): 6122-6127. 
23. Loebel A., et al. “Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar i depression: A randomized, double-blind, placebo-controlled study”. American Journal of Psychiatry 171 (2014): 169-177.
24. Huang X., et al. “Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) in cancer”. Journal of Hematology and Oncology 11.1 (2018): 88.
25. Thompson M., et al. “Crosstalk of the Wnt Signaling Pathway”. In: Goss K., Kahn M. (eds) Targeting the Wnt Pathway in Cancer. Springer, New York, NY (2011). 
26. Liao X., et al. “Aberrant activation of hedgehog signaling pathway contributes to endometrial carcinogenesis through β-catenin”. Modern Pathology 22 (2009): 839-847.
27. Maeda O., et al. “Enhancement of GLI1-transcriptional activity by β-catenin in human cancer cells’. Oncology Reports 16 (2006): 91-96.
28. Teissedre B., et al. “MMTV-Wnt1 and -ΔN89β-Catenin Induce Canonical Signaling in Distinct Progenitors and Differentially Activate Hedgehog Signaling within Mammary Tumors”. PLoS One 4.3 (2009): 10.
29. Noubissi FK., et al. “Role of CRD-BP in the growth of human basal cell carcinoma cells”. Journal of Investigative Dermatology 134.6 (2014): 1718-1724. 
30. Williams CS., et al. “Sulindac Sulfide, but not Sulindac Sulfone, Inhibits Colorectal Cancer Growth”. Neoplasia 1.2 (1999): 170-176.

Citation

Citation: Ratna Kumari., et al. “The Therapeutic Relevance of Co-Targeting Wnt-Hh Signalling Pathways in Hepatocellular Carcinoma”. Acta Scientific Gastrointestinal Disorders 3.3 (2020): 32-40.

Copyright

Copyright: © 2020 Ratna Kumari., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.