RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma

Akula, Shaw M.; Abrams, Stephen L.; Steelman, Linda S.; Emma, Maria Rita; Augello, Giuseppa; Cusimano, Antonella; Azzolina, Antonina; Montalto, Giuseppe; Cervello, Melchiorre; McCubrey, James A.

doi:10.1080/14728222.2019.1685501

Cited by 67 publications

(47 citation statements)

References 104 publications

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“…In HCC tissue, mTORC1 is highly activated [413][414][415][416]. Loss of BCAA catabolism during carcinogenesis enhances mTORC1 activity and promotes tumor development and progression [414,415].…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Melnik

2021

Biomolecules

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The consumption of cow’s milk is a part of the basic nutritional habits of Western industrialized countries. Recent epidemiological studies associate the intake of cow’s milk with an increased risk of diseases, which are associated with overactivated mechanistic target of rapamycin complex 1 (mTORC1) signaling. This review presents current epidemiological and translational evidence linking milk consumption to the regulation of mTORC1, the master-switch for eukaryotic cell growth. Epidemiological studies confirm a correlation between cow’s milk consumption and birthweight, body mass index, onset of menarche, linear growth during childhood, acne vulgaris, type 2 diabetes mellitus, prostate cancer, breast cancer, hepatocellular carcinoma, diffuse large B-cell lymphoma, neurodegenerative diseases, and all-cause mortality. Thus, long-term persistent consumption of cow’s milk increases the risk of mTORC1-driven diseases of civilization. Milk is a highly conserved, lactation genome-controlled signaling system that functions as a maternal-neonatal relay for optimized species-specific activation of mTORC1, the nexus for regulation of eukaryotic cell growth, and control of autophagy. A deeper understanding of milk´s impact on mTORC1 signaling is of critical importance for the prevention of common diseases of civilization.

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Section: Hepatocellular Carcinomamentioning

confidence: 99%

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Melnik

2021

Biomolecules

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“…The nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1) is overactivated in many cancers including HCC (70)(71)(72)(73)(74)(75)(76)(77)(78)(79). Not only insulin and IGF-1 activate mTORC1 but also AAs (80,81), preferentially the BCAAs leucine, isoleucine and valine (82)(83)(84)(85)(86)(87)(88).…”

Section: Bcaasmentioning

confidence: 99%

“…Obviously, the type of model, target cells and stage of HCC development are of importance for HCC-promoting or HCC-preventing effects of BCAAs. Nevertheless, BCAA-mediated activation of hepatic mTORC1 is generally accepted to promote HCC development, progression and spreading (78,79,335,336). Activation of mTOR is more intense in the tumor edge, reinforcing its role in HCC proliferation and spreading (336).…”

Section: Liver Cirrhosis and Advanced Hccmentioning

confidence: 99%

Dairy consumption and hepatocellular carcinoma risk

Melnik¹

2021

Ann Transl Med

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This review provides epidemiological and translational evidence for milk and dairy intake as critical risk factors in the pathogenesis of hepatocellular carcinoma (HCC). Large epidemiological studies in the United States and Europe identified total dairy, milk and butter intake with the exception of yogurt as independent risk factors of HCC. Enhanced activity of mechanistic target of rapamycin complex 1 (mTORC1) is a hallmark of HCC promoted by hepatitis B virus (HBV) and hepatitis C virus (HCV). mTORC1 is also activated by milk protein-induced synthesis of hepatic insulin-like growth factor 1 (IGF-1) and branched-chain amino acids (BCAAs), abundant constituents of milk proteins. Over the last decades, annual milk protein-derived BCAA intake increased 3 to 5 times in Western countries. In synergy with HBV-and HCV-induced secretion of hepatocyte-derived exosomes enriched in microRNA-21 (miR-21) and miR-155, exosomes of pasteurized milk as well deliver these oncogenic miRs to the human liver. Thus, milk exosomes operate in a comparable fashion to HBV-or HCV-induced exosomes. Milk-derived miRs synergistically enhance IGF-1-AKT-mTORC1 signaling and promote mTORC1-dependent translation, a meaningful mechanism during the postnatal growth phase, but a long-term adverse effect promoting the development of HCC. Both, dietary BCAA abundance combined with oncogenic milk exosome exposure persistently overstimulate hepatic mTORC1. Chronic alcohol consumption as well as type 2 diabetes mellitus (T2DM), two HCC-related conditions, increase BCAA plasma levels. In HCC, mTORC1 is further hyperactivated due to RAB1 mutations as well as impaired hepatic BCAA catabolism, a metabolic hallmark of T2DM. The potential HCC-preventive effect of yogurt may be caused by lactobacilli-mediated degradation of BCAAs, inhibition of branched-chain α-ketoacid dehydrogenase kinase via production of intestinal medium-chain fatty acids as well as degradation of milk exosomes including their oncogenic miRs. A restriction of total animal protein intake realized by a vegetable-based diet is recommended for the prevention of HCC.

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“…Previous reports have indicated the importance of miRNAs in modulating cancer-related Correspondence: Wencai Wang Email wangwencai00001@126.com signaling pathways. 8,9 Additionally, miRNAs may be related to types of malignant tumors and serve as key factors for tumorigenesis of many cancers. 10 However, the function of miRNAs during the progression of EC remains to be understood.…”

Section: Introductionmentioning

confidence: 99%

<p>Downregulation of miR-7-5p Inhibits the Tumorigenesis of Esophagus Cancer via Targeting KLF4</p>

Shi¹,

Song²,

Gao³

et al. 2020

OTT

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Background: Esophageal cancer (EC) is one of the aggressive gastrointestinal malignancies. It has been reported that microRNAs (miRNAs) play key roles during the tumorigenesis of EC. To identify novel potential targets for EC, differential expressed miRNAs (DEG) between EC and adjacent normal tissues were analyzed with bioinformatics tool. Methods: The differential expression of miRNAs between EC and adjacent normal tissues was analyzed. CCK-8 and Ki67 staining were used to detect the cell proliferation. Flow cytometry was performed to test the cell apoptosis. The correlation between miR-7-5p and KLF4 was detected by dual-luciferase report assay. Gene and protein expression in EC cells or in tissues were measured by qRT-PCR and Western blot, respectively. Cell migration and invasion were detected with transwell assay. Xenograft mice model was established to investigate the role of miR-7-5p in EC tumorigenesis in vivo. Results: MiR-7-5p was found to be negatively correlated with the survival rate of patient with EC. In addition, downregulation of miR-7-5p significantly inhibited the growth and invasion of EC cells. Meanwhile, miR-7-5p directly targeted KLF4 in EC cells. Moreover, downregulation of miR-7-5p inhibited the tumorigenesis of EC via inactivating MAPK signaling pathway in vivo. Conclusion: Downregulation of miR-7-5p notably suppressed the progression of EC via targeting KLF4. Thus, miR-7-5p might serve as a new target for the treatment of EC.

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RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma

Cited by 67 publications

References 104 publications

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Lifetime Impact of Cow’s Milk on Overactivation of mTORC1: From Fetal to Childhood Overgrowth, Acne, Diabetes, Cancers, and Neurodegeneration

Dairy consumption and hepatocellular carcinoma risk

<p>Downregulation of miR-7-5p Inhibits the Tumorigenesis of Esophagus Cancer via Targeting KLF4</p>

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