Michael Shearer

Background: Hepatocellular carcinoma (HCC) is a primary liver cancer comprising 75-85% of liver cancers globally in 2020¹. Its most common risk factors include hepatitis B, hepatitis C, alcohol abuse, and chronic illnesses such as diabetes mellitus type 2 and obesity^1,2. Common treatments are surgical resection, liver transplantation, image-guided ablation, transcatheter arterial chemoembolization, and chemotherapy^2,3. Late detection often renders resection impossible^3,4. Sorafenib is the first-line drug to treat HCC⁵. It is a multikinase inhibitor thought to inhibit cell proliferation and angiogenesis⁶. Circular RNAs (circRNAs) are noncoding covalent continuous loops with no 5’ to 3’ polarity or polyadenylated tail³. In HCC, in vitro models support circRNAs as modulators of the PI3K/AKT/mTOR pathway^5,7.

Objectives: In this review, we sought to elucidate common modulators of the PI3K/AKT/mTOR pathway in HCC and how these may serve as potential therapeutic targets to improve early tumor detection and clinical outcomes.

Search Methods: An online search was conducted using the PubMed database using the phrase “hepatocellular carcinoma” from 2018 – 2023. MeSH terms applied were “diagnosis,” “etiology,” “genetics,” “pathology,” and “pathophysiology.”

Results: circZKSCAN1 was downregulated in HCC⁵. HCC cells treated with sorafenib showed increased expression of circZKSCAN1⁵. circZKSCAN1-knockout cells treated with sorafenib showed decreased apoptosis, suggesting loss of circZKSCAN1 as a mechanism of sorafenib resistance⁵. While circRNAs are thought to be noncoding, circZKSCAN1 contains an internal ribosomal entry site⁵. In cells overexpressing the translated peptide circZKSaa, ubiquitinated mTOR and inhibition of anti-apoptotic proteins was observed⁵. circRPN2 is also downregulated in HCC⁷. Decreased circRPN2 expression yielded increased cell proliferation, colony formation, and migration while overexpression showed the opposite results⁷. circRPN2-knockdown cells had high levels of p-AKT and p-mTOR, with the opposite result for those overexpressing circRPN2⁷. circRPN2-knockdown conditions reduced cellular respiration and increased glycolysis while overexpression produced the opposite effect⁷. PDK1 and PI3K expression was found to be upregulated in HCC by in silico protein transcriptomic analysis⁸. When given increasing doses of radiotherapy, HCC cells with the highest levels of PDK1 expression were most resistant⁸. siRNA-mediated loss of PDK1 showed increased sensitivity to radiotherapy and decreased levels of phosphorylated and dephosphorylated PI3K, AKT, mTOR⁸. This suggests PDK1 signaling as a driver of dysregulation of the PI3K/AKT/mTOR pathway⁸. Downstream of mTOR, NEAT1 relative expression was elevated in HCC cells given the mTORC1 inhibitor rapamycin, supporting direct influence of mTORC1 on NEAT1 levels⁹. Luciferase assays demonstrated mTORC1 acting as a repressor of NEAT1, whose expression also increased in a low glucose environment⁹. mTORC1 downregulates NEAT1, allowing free NONO to assemble in the RNA spliceosome and increase glycolysis⁹. Clinically, in patients with recurrent HCC post-liver transplantation, mTOR inhibitors showed increased survival, with univariate analysis revealing only time of tumor recurrence and mTOR inhibitor use as statistically significant¹⁰.

Conclusion: Multifactorial modulation of the PI3K/AKT/mTOR pathway is key in conferring increased tumorigenesis and aggression of HCC. Therapy that targets the PI3K/AKT/mTOR pathway, whether by direct means or indirect such as upregulation of key circRNAs, is a promising approach to improving outcomes.

Works Cited

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2. Zhang Q, Li H, Liu Y, Li J, Wu C, Tang H. Exosomal Non-Coding RNAs: New Insights into the Biology of Hepatocellular Carcinoma. Curr Oncol Tor Ont. 2022;29(8):5383-5406. doi:10.3390/curroncol29080427
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