Alpha1-ACT Functions as a Tumour Suppressor in Hepatocellular Carcinoma by Inhibiting the PI3K/AKT/mTOR Signalling Pathway via Activation of PTEN

Abstract

Background & Aims: To investigate the expression and prognostic value of α1-ACT (Alpha1-antichymotrypsin) in patients with HCC (hepatocellular carcinoma) and identify the mechanism by which α1-ACT inhibits proliferation and promotes apoptosis of HCC. Methods: We first measured α1-ACT expression levels and determined their relationship with the clinicopathological characteristics and prognosis of patients with HCC.We then established stable HCC cell lines with both α1-ACT overexpression and knockdown and performed a functional analysis in vitro.We first examined the relationship between α1-ACT and the PTEN/PI3K/AKT/mTOR pathway using Western blotting. Then, we determined whether α1-ACT can directly bind to PTEN using co-immunoprecipitation. Finally, we measured α1-ACT expression to evaluate its correlation with the PI3K/AKT/mTOR pathway-related apoptosis proteins in a xenograft tumour mouse model using immunohistochemistry. Results: The α1-ACT expression level was significantly lower in the HCC tissues than in the paratumour tissues and was negatively positively correlated with the level of Ki67, AFP, the AJCC stage, tumour size and tumour invasion. The overexpression of α1-ACT can inhibit cell proliferation and increase cell apoptosis by activating PI3K/AKT/mTOR-mediated apoptosis via binding to PTEN and activating it in vitro. Additionally, the overexpression of α1-ACT can also increase the proportion of cells in the G0/G1 stage by increasing cyclin p21 expression and inhibiting the migration and invasion abilities of HCC cells by regulating MMP2 and MMP9. The xenotransplantation studies with nude mice also showed that overexpression of α1-ACT inhibited tumourigenesis and knockdown of α1-ACT had the opposite effect. Conclusions: Our study demonstrates that α1-ACT suppresses liver cancer development and metastasis via targeting the PTEN/PI3K/AKT/mTOR signalling pathway, which may be a potential target for therapeutic intervention in HCC.

MicroRNA-92a-3p enhances functional recovery and suppresses apoptosis after spinal cord injury via targeting phosphatase and tensin homolog

“…It has previously been demonstrated that PTEN functions as an inhibitor to AKT/mTOR pathway in many cancers [10,24]. In our study, miR-92a-3p directly targeted PTEN, thus, we speculated whether miR-92a-3p contributed to the activation of AKT/mTOR pathway through targeting PTEN.…”

“…In AKT/mTOR pathway, phosphoinositide 3-kinases (PI3Ks) convert phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3), subsequently activates Akt, mTOR and ribosomal protein (S6), ultimately realizing its neuroprotective effects [43]. However, after SCI, the up-regulation of PTEN can obviously reverse the conversion of PIP2 into PIP3, leading to the inactivation of AKT/mTOR pathway [10]. We also detected the up-regulation of PTEN in the spinal cord tissues derived from the mice after SCI.…”

“…Phosphatase and tensin homolog (PTEN) has potent ability in regulating cell growth and proliferation, and is identified as a promising tumor suppressor [9][10][11]. In addition to anti-tumor effect, PTEN also plays a particularly important role in regulating axon regeneration after SCI [12].…”

miRNA‐216 knockdown has effects to suppress osteosarcoma via stimulating PTEN

“…It is an important protein in tumor invasive growth. MMP2/9 was also an important downstream gene of PTEN/PI3K/AKT pathway (Li et al., 2013; Zhu et al., 2017). By double luciferase assay, we confirmed that PTEN was the target gene of miRNA‐216.…”

2-Methyl 2-butanol suppresses human retinoblastoma cells through cell cycle arrest and autophagy

“…The abnormal P13K/AKT/mTOR signaling pathway leads to reduce apoptosis and increase proliferation and is the main cause of cell carcinogenesis, tumor invasion, metastasis, and drug resistance. The abnormalities of this signaling pathway are common in breast cancer, lung cancer, liver cancer, melanoma, cervical cancer, and rhabdomyosarcoma ( 8 – 12 ). Therefore, the investigation of P13K/AKT signaling pathway in retinoblastoma cells would be helpful to develop a new strategy to treat retinoblastoma.…”