Eph/Ephrin family, one of the largest receptor tyrosine kinase families, has been extensively studied in morphogenesis and neural development. Recently, growing attention has been paid to its role in the initiation and progression of various cancers. However, the role of Eph/Ephrins in hepatocellular carcinoma (HCC) has been rarely investigated. In this study, we found that the expression of EphrinA2 was significantly up-regulated in both established cell lines and clinical tissue samples of HCC, and the most significant increase was observed in the tumors invading the portal veins. Forced expression of EphrinA2 in HCC cells significantly promoted in vivo tumorigenicity, whereas knockdown of this gene inhibited this oncogenic effect. We further found that suppression of apoptosis, rather than accelerating proliferation, was responsible for EphrinA2-enhanced tumorigenicity. In addition, EphrinA2 endowed cancer cells with resistance to tumor necrosis factor alpha (TNF-␣)-induced apoptosis, thus facilitating their survival. Furthermore, we disclosed a novel EphrinA2/ras-related c3 botulinum toxin substrate 1 (Rac1)/V-akt murine thymoma viral oncogene homolog ( H epatocellular carcinoma (HCC) is a major health problem worldwide, ranking as the fifth most common cancer in the world and the third most common cause of cancer-related death. 1 HCC shows great geographical variation, with a very high incidence in Asia and sub-Saharan Africa, but it is now becoming more common in the West. During the past 20 years in the United States, HCC has risen by 114%. 2 This paralleled an increase in the incidence of chronic hepatitis, which serves as a main risk factor for HCC. 3 At the initiation of hepatic oncogenesis, transformed hepatocytes must elude various cellular defense activities and acquire abnormal capabilities to survive and proliferate. 4 Aberrant signaling through receptor tyrosine kinases plays a pivotal role in the development and progression of HCC. 5 Eph receptors constitute one of the largest receptor tyrosine kinase families and have been reported to be involved in a variety of cancers. For example, up-regulation of EphA2 has been observed in many malignant tumors [6][7][8] and is associated with accelerated cell prolifera-
Obesity increases the risks of steatosis, non-alcoholic steatohepatitis (NASH) and HCC development. Non-alcoholic fatty liver disease (NAFLD) associated-hepatocellular carcinoma (HCC) is a male-predominant cancer mainly caused by metabolic disorder. Our previous findings demonstrated that cell cycle-related kinase (CCRK), through upregulates mTORC1 pathway, resulting in deregulated lipid/glucose metabolism and tumorigenesis (Nat Communs accepted). In this study, we further elucidate that CCRK activates mTORC1 through SLC3A2 and SLC7A5 dependent amino acid transportation. We performed comprehensive immune cell profiling in a high-fat high-carbohydrate diet (HFHC)-induced obesity and NASH murine model and uncovered activation of CCRK-mTORC1 signaling cascade and specific induction of myeloid-derived suppressor cell (MDSC), reduction in CD8+ T cells, which subsequently enhanced tumor growth of orthotopically-implanted HCC tumor cells. Notably, treatment of the mTORC1/C2 dual kinase inhibitor vistusertib (AZD2014), currently undergone phase I/II clinical trials, abrogated mTORC1/SREBP2 signaling and metabolic dysregulation especially cholesterol levels. Further immune profiling in liver and blood of AZD2014 treated mice will be performed. Furthermore, mTORC1/SREBP2 positively associated with cholesterol level in the streptozotocin (STZ)-HFHC induced spontaneous NAFLD-HCC mouse model, which will be utilized to further study the therapeutic effect of vistusertib in vivo. Collectively, this study will elucidate the metabolic-immunosuppressive role of CCRK-mTOR signaling in NAFLD-associated HCC and further provide insights into development of therapeutic strategies against the CCRK-mTOR reinforced NAFLD-HCC. This project is supported by Collaborative Research Fund C4017-14G and the Focused Innovations Scheme 1907309. Citation Format: Wenshu TANG, Jingying ZHOU, Weiqin YANG, Yu FENG, Myth MOK, Alfred Sze CHENG. Metabolic-immunoregulatory role of CCRK-mTOR signaling in NAFLD-associated hepatocellular carcinoma [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 2804.
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