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      PTTG1 Reprograms Asparagine Metabolism to Promote Hepatocellular Carcinoma Progression

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          Abstract

          Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has a poor prognosis. Pituitary tumor transforming gene 1 (PTTG1) is highly expressed in HCC, suggesting it could play an important role in hepatocellular carcinogenesis. Here, we evaluated the impact of PTTG1 deficiency on HCC development using a diethylnitrosamine (DEN)-induced HCC mouse model and a hepatitis B virus (HBV) regulatory X protein (HBx)–induced spontaneous HCC mouse model. PTTG1 deficiency significantly suppressed DEN- and HBx-induced hepatocellular carcinogenesis. Mechanistically, PTTG1 promoted asparagine synthetase (ASNS) transcription by binding to its promoter, and asparagine (Asn) levels were correspondingly increased. The elevated levels of Asn subsequently activated the mTOR pathway to facilitate HCC progression. In addition, asparaginase treatment reversed the proliferation induced by PTTG1 overexpression. Furthermore, HBx promoted ASNS and Asn metabolism by upregulating PTTG1 expression. Overall, PTTG1 is involved in the reprogramming of Asn metabolism to promote HCC progression and may serve as a therapeutic and diagnostic target for HCC.

          Significance:

          PTTG1 is upregulated in hepatocellular carcinoma and increases asparagine production to stimulate mTOR activity and promote tumor progression.

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          Most cited references55

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          The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism

          The altered metabolic programme of cancer cells facilitates their cell-autonomous proliferation and survival. In normal cells, signal transduction pathways control core cellular functions, including metabolism, to couple the signals from exogenous growth factors, cytokines or hormones to adaptive changes in cell physiology. The ubiquitous, growth factor-regulated phosphoinositide 3-kinase (PI3K)-AKT signalling network has diverse downstream effects on cellular metabolism, through either direct regulation of nutrient transporters and metabolic enzymes or the control of transcription factors that regulate the expression of key components of metabolic pathways. Aberrant activation of this signalling network is one of the most frequent events in human cancer and serves to disconnect the control of cell growth, survival and metabolism from exogenous growth stimuli. Here we discuss our current understanding of the molecular events controlling cellular metabolism downstream of PI3K and AKT and of how these events couple two major hallmarks of cancer: growth factor independence through oncogenic signalling and metabolic reprogramming to support cell survival and proliferation.
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            The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level : Results From the Global Burden of Disease Study 2015

            Importance Liver cancer is among the leading causes of cancer deaths globally. The most common causes for liver cancer include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and alcohol use. Objective To report results of the Global Burden of Disease (GBD) 2015 study on primary liver cancer incidence, mortality, and disability-adjusted life-years (DALYs) for 195 countries or territories from 1990 to 2015, and present global, regional, and national estimates on the burden of liver cancer attributable to HBV, HCV, alcohol, and an “other” group that encompasses residual causes. Design, Settings, and Participants Mortality was estimated using vital registration and cancer registry data in an ensemble modeling approach. Single-cause mortality estimates were adjusted for all-cause mortality. Incidence was derived from mortality estimates and the mortality-to-incidence ratio. Through a systematic literature review, data on the proportions of liver cancer due to HBV, HCV, alcohol, and other causes were identified. Years of life lost were calculated by multiplying each death by a standard life expectancy. Prevalence was estimated using mortality-to-incidence ratio as surrogate for survival. Total prevalence was divided into 4 sequelae that were multiplied by disability weights to derive years lived with disability (YLDs). DALYs were the sum of years of life lost and YLDs. Main Outcomes and Measures Liver cancer mortality, incidence, YLDs, years of life lost, DALYs by etiology, age, sex, country, and year. Results There were 854 000 incident cases of liver cancer and 810 000 deaths globally in 2015, contributing to 20 578 000 DALYs. Cases of incident liver cancer increased by 75% between 1990 and 2015, of which 47% can be explained by changing population age structures, 35% by population growth, and −8% to changing age-specific incidence rates. The male-to-female ratio for age-standardized liver cancer mortality was 2.8. Globally, HBV accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), HCV for 167 000 (21%), and other causes for 133 000 (16%) deaths, with substantial variation between countries in the underlying etiologies. Conclusions and Relevance Liver cancer is among the leading causes of cancer deaths in many countries. Causes of liver cancer differ widely among populations. Our results show that most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use. In line with the Sustainable Development Goals, the identification and elimination of risk factors for liver cancer will be required to achieve a sustained reduction in liver cancer burden. The GBD study can be used to guide these prevention efforts. This data analysis of the Global Burden of Disease 2015 study on primary liver cancer reports incidence, mortality, and disability-adjusted life-years for 195 countries or territories from 1990 to 2015, and presents global, regional, and national estimates on the burden of liver cancer. Question What is the burden of liver cancer globally, what are the major risk factors for liver cancer across countries, regions, and at the global level and how did these change between 1990 and 2015? Findings There were 854 000 incident liver cancer cases and 810 000 deaths globally in 2015, contributing to 20 578 000 disability-adjusted life-years. Hepatitis B virus infection accounted for 265 000 liver cancer deaths (33%), alcohol for 245 000 (30%), hepatitis C virus infection for 167 000 (21%), and other causes for 133 000 (16%) deaths. Meaning Most cases of liver cancer can be prevented through vaccination, antiviral treatment, safe blood transfusion and injection practices, as well as interventions to reduce excessive alcohol use.
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              Metabolic reprogramming: a cancer hallmark even warburg did not anticipate.

              Cancer metabolism has long been equated with aerobic glycolysis, seen by early biochemists as primitive and inefficient. Despite these early beliefs, the metabolic signatures of cancer cells are not passive responses to damaged mitochondria but result from oncogene-directed metabolic reprogramming required to support anabolic growth. Recent evidence suggests that metabolites themselves can be oncogenic by altering cell signaling and blocking cellular differentiation. No longer can cancer-associated alterations in metabolism be viewed as an indirect response to cell proliferation and survival signals. We contend that altered metabolism has attained the status of a core hallmark of cancer. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Cancer Research
                American Association for Cancer Research (AACR)
                0008-5472
                1538-7445
                July 14 2023
                May 09 2023
                July 14 2023
                May 09 2023
                : 83
                : 14
                : 2372-2386
                Article
                10.1158/0008-5472.CAN-22-3561
                37159932
                6b448d8e-df7d-47cc-b759-e40455b2b3c0
                © 2023
                History

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