LaShawn Oyibo

Background: Hepatocellular carcinoma (HCC) is a primary liver cancer that develops from hepatocytes, which are the liver’s parenchymal cells.¹ It is the most common primary liver cancer and is also the fifth most common type of cancer, accounting for almost 10% of all cancer cases.² Current treatments for HCC are limited due to HCC not typically being diagnosed until it has already reached an advanced stage. ^3,4 Updated treatments are currently needed to improve prognosis and broaden options for patients. Aberrant activation of the PI3K-AKT pathway significantly contributes to the invasion and metastasis of tumor cells in HCC.³ Similarly, aberrant activation of the hedgehog signaling pathway past the point of liver development contributes significantly to the invasiveness of HCC.^3,5 While the dysregulated hedgehog and PI3K-AKT signaling pathways and their related transcription factors have been shown to contribute to the development of HCC, their exact relationship to one another is still unknown.³ Identification of the relationship between these two pathways could potentially lead to new therapeutic targets.

Objective: In this review, we examined the PI3K-AKT and hedgehog signaling pathways and how their aberrant activations were related to the development of hepatocellular carcinoma.

Search Methods: An online search of the PubMed database was conducted from 2017 to 2023 using “hepatocellular carcinoma,” “PI3K-AKT pathway,” “hedgehog pathway,” “aberrant signaling,” and “transcription factor overexpression” as keywords.

Results: Studies determined that the presence of transcription factors such as GLI1, SHH, and AKT known to be involved in either the hedgehog or PI3K-AKT pathway were significantly higher in tumor cells than in non-cancerous cells.³ The effects of SHH gene knockdown resulted in several effects on the HCC cells. First, it was determined that significantly fewer colonies were detected in the HCC cells because anchorage-independent growth of the HCC cells was reduced.⁵ Additionally, cell proliferation of the HCC cells was reduced at each time point when tested with an MTT assay.⁵ Additional studies found that when Vismodegib, a hedgehog ligand inhibitor, and Entinostat, a histone deacetylase inhibitor, were used in combination, there was a synergistic induction of apoptosis in liver cancer cells.³ There was also a synergistic increase in liver cancer cell proliferation when the two drugs were jointly used.³ Lastly, ARHGAP20 was recently identified as a tumor suppressor gene and was found to be downregulated with aberrant activation of the PI3K-AKT pathway.⁶ Studies have indicated that upregulation of ARHGAP20 can suppress activation of the PI3K-AKT pathway by inhibiting the necessary phosphorylation of the AKT transcription factor.⁶

Conclusion: Studies have found that combined use of Vismodegib and Entinostat are effective in suppressing the growth of liver cancer through increased apoptotic activity and increased inhibition of cell proliferation. Furthermore, upregulation of the tumor suppressor gene ARHGAP20 has been shown to suppress the activation of the PI3K-AKT pathway. Further research still needs to be conducted to determine the relationship between the hedgehog and PI3K-AKT signaling pathways so that a potential therapy can be developed targeting that relationship.

Works Cited:

1. Chidambaranathan-Reghupaty S, Fisher PB, Sarkar D. Hepatocellular carcinoma (HCC): Epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61. doi:10.1016/bs.acr.2020.10.001
2. Sagnelli E, Macera M, Russo A, Coppola N, Sagnelli C. Epidemiological and etiological variations in hepatocellular carcinoma. Infection. 2020;48(1):7-17. doi:10.1007/s15010-019-01345-y
3. Chen B, Hu Z, Li B, Lin X, Luo Z, Hu Z. The expressions of Hedgehog and PI3K- AKT pathway components correlate with invasion and metastasis in hepatocellular carcinoma. Int J Clin Exp Pathol. 2019;12(6):2381-2388. Published 2019 Jun 1.
4. Li J, Cai H, Li H, et al. Combined inhibition of sonic Hedgehog signaling and histone deacetylase is an effective treatment for liver cancer. Oncol Rep. 2019;41(3):1991-1997. doi:10.3892/or.2019.6982
5. Chen Y, Zhu W. Knockdown of the Sonic Hedgehog (SHH) Gene Inhibits Proliferation of Hep3B and SMMC-7721 Hepatocellular Carcinoma Cells via the PI3K/Akt/PCK1 Signaling Pathway. Med Sci Monit. 2019;25:6023-6033. Published 2019 Aug 13. doi:10.12659/MSM.914768
6. Liu G, Li J, Zhang CY, Huang DY, Xu JW. ARHGAP20 Expression Inhibited HCC Progression by Regulating the PI3K-AKT Signaling Pathway. J Hepatocell Carcinoma. 2021;8:271-284. Published 2021 Apr 21. doi:10.2147/JHC.S298554