PI3Kδ Is a Therapeutic Target in Hepatocellular Carcinoma

Abstract

Class I phosphoinositide 3‐kinase (PI3K) signaling is a major pathway in human cancer development and progression. Among the four PI3K isoforms, PI3Kα and PI3Kβ are ubiquitously expressed, whereas PI3Kγ and PI3Kδ are found primarily in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3Kα‐mediated and PI3Kβ‐mediated cancer cell–intrinsic PI3K activity. The role of PI3Kδ in solid tumors is unknown. Here, we evaluated the effects of PI3Kδ using established hepatocellular carcinoma (HCC) cells, malignant hepatocytes derived from patients with advanced HCC, murine models, and HCC tissues using RNA sequencing, quantitative PCR, immunoblotting, immunofluorescence, microarray, liquid chromatography–tandem mass spectrometry, and kinase assay. We established a chemical carcinogenesis model of liver malignancy that reflects the malignant phenotype and the in vivo environment of advanced HCC. In this in vivo advanced HCC‐mimic system using HCC cells treated with hydrogen peroxide (H2O2), we showed that H2O2 selectively increases PI3Kδ activity while decreasing that of other class I PI3Ks. Blocking PI3Kδ activity with a PI3Kδ inhibitor or small interfering RNA–mediated PI3Kδ gene silencing inhibited HCC‐cell proliferation and dampened key features of malignant HCC, including the up‐regulation of telomerase reverse transcriptase (TERT). Mechanistically, H2O2 induced oxidative modification of the serpin peptidase inhibitor, serpin peptidase inhibitor (SERPINA3), blocking its ubiquitin‐dependent degradation and enhancing its activity as a transcriptional activator of PI3Kδ and TERT. High PI3Kδ levels in HCC were found to correlate with poor survival rates, with human advanced HCC showing positive correlations between the protein levels of oxidized SERPINA3, PI3Kδ, and TERT. Thus, PI3Kδ plays significant roles in malignant liver tumors. Conclusion: Our data identify PI3Kδ inhibition, recently approved for the treatment of human B‐cell malignancies, as a potential treatment for HCC.

The Target MicroRNAs and Potential Underlying Mechanisms of Yiqi-Bushen-Tiaozhi Recipe against‐Non-Alcoholic Steatohepatitis

“…Previous studies on p110δ mutant mice showed that p110δ-Akt pathway plays a key role in HFD-induced inflammatory response (Mauro et al, 2017). High PI3Kδ expression level was found high in HCC and it plays significant roles in HCC (Ko et al, 2018). MSN encodes the moesin protein.…”

PI3K isoforms in cell signalling and vesicle trafficking

“…p110δ is also found in neurons 75,76 and fibroblast-like cells 77,78 with functions in axonal transport 79 and inflammatory responses 77 , respectively. p110δ can also become highly expressed in some solid tumour types, such as breast 80,81 and liver 82,83 , with emerging evidence that it could be a therapeutic target in these cancers 81-83 . 5 Another parameter in isoform-selective function of PI3K isoforms is their differential capacity to respond to specific upstream signals (FIG.…”

Phosphoinositide 3-kinase inhibitors are effective therapeutic drugs for the treatment of hepatocellular carcinoma?

“…2 Several studies have reported that upregulation of PI3Kδ is positively correlated with progression of human advanced cancers such as HCC and melanoma. 3,4 Moreover, Idelalisib is well-known as a first-in-class PI3Kδ inhibitor for the treatment of leukemia. 5 Recently, it has been reported that Idelalisib suppresses HCC progression.…”

“…5 Recently, it has been reported that Idelalisib suppresses HCC progression. 4 Subsequently, high expression levels of PI3Kδ have been associated with advanced HCC. 4 However, PI3Kδ expression levels in Huh7-BAT and HepG2 cell lines have not been shown in this study.…”

“…4 Subsequently, high expression levels of PI3Kδ have been associated with advanced HCC. 4 However, PI3Kδ expression levels in Huh7-BAT and HepG2 cell lines have not been shown in this study. It is crucial to elucidate the effects of PI3Kδ inhibitor on HCC progression.…”