Abstract 1721: FOXO1, a downstream substrate of AKT, function as tumor suppressor in HCC carcinogenesis

Abstract

Abstract Hepatocellular carcinoma (HCC) represents the fifth most common tumor types in the world and the third leading cause of cancer-related death. However, the signaling pathways underlying hepatic pathogenesis are still poorly understood, hence lacking of effective targeted therapy. Activation of PI3K/AKT signaling cascade has been implicated in HCC development. It has been well-established that the mammalian target of rapamycin complex 1 (mTORC1), is a major downstream effector of AKT. The reason why mTORC1 can be consistently activated is partly due to inactive mutations of a negative element regulating mTORC1, tuberous sclerosis 2 (TSC2), found in 10% human HCCs. Beyond TSC2, forkhead Box O transcription factor 1 (FOXO1), is another AKT substrate. It has been proved that FOXO1 plays a crucial role in the insulin signal pathway and liver regeneration relying on AKT isoforms. However, the role of FOXO1 in HCC development has not been well established. Here we report, by using TCGA database the mRNA level of FOXO1 significantly decreases among the FOXO family, comparing tumor tissue to the surrounding tissue. The overall survival rate favors patients with high FOXO1 expression level. The inhibition efficacies of a pan-AKT inhibitor, in both TSC2 wide type cells and TSC2-null ones, indicating TSC2 is not the only target downstream of AKT. Protein analysis shows the activity of mTORC1 can still be inhibited as well as the phosphorylation of FOXO1 in TSC2-null cells. Therefore, we hypothesize that in the presence of TSC2, AKTi can suppress the activation of mTORC1 directly through TSC2. Otherwise, in the absence of TSC2, AKTi can still inhibit mTORC1 via activation of FOXO1. Furthermore, we overexpress the activated FOXO1 (FOXO1 AAA) in TSC2-null HCC cell lines. Cell growth are significantly prohibited, implicating FOXO1 is a tumor suppressor in HCC cells. Over expression of activated FOXO1 can also delay mTORC1 activation based HCC in AKT/Ras FVB mice model.Lesions consist mainly of clear-cell hepatocytes, owing to an increase in glycogen and fat storage. Proliferation is nearly the same within the neoplastic nodules. Activated AKT occurs both in the cytoplasm and on the membrane. Interestingly, FOXO1AAA escapes into the cytoplasm instead of remaining in the nuclei where it should stay. In a conclusion, AKT/mTORC1 can be a classic molecular pathway for HCC pathogenesis. Nevertheless, the parallel substrate of AKT, FOXO1, may also be an important factor in a TSC2 independent way. Citation Format: Shu Zhang, Xin Chen. FOXO1, a downstream substrate of AKT, function as tumor suppressor in HCC carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1721.