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Here, we highlight the importance that have these miRNAs   JE, Ratziu V, McCullough A. Endpoints and clinical trial design for
            as repressor of factors coordinating the cell fate by triggering   nonalcoholic steatohepatitis. Hepatology 2011;54:344-53.
            pro-death mechanisms e.g. apoptosis and autophagy.  5.   Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function.
                                                                  Cell 2004;116:281-97.
                                                              6.   Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC
            In particular, the authors reported that AMP-activated protein   couples microRNA biogenesis and posttranscriptional gene silencing.
            kinase (AMPK) is a target of the majority of the identified   Cell 2005;123:631-40.
            miRNAs. AMPK is responsible of metabolic processes as   7.   Cheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum
            mentioned  by  the  authors,  thus  conferring  it  also  a  key   JM, Min H, Luketic  VA, Sanyal AJ. Nonalcoholic steatohepatitis is
                                                                  associated with altered hepatic microRNA expression.  Hepatology
            role during autophagy.  In particular, AMPK is responsible   2008;48:1810-20.
                              [12]
            of  ULK1  (serine/threonine-protein  kinase)  phosphorylation   8.   Pogribny IP,  Starlard-Davenport A,  Tryndyak  VP,  Han  T,  Ross  SA,
            with consequent mammalian target of rapamycin complex   Rusyn I, Beland FA. Difference in expression of hepatic microRNAs
            (mTORC) inhibition and autophagy activation during    miR-29c, miR-34a, miR-155, and miR-200b is associated with strain-
            nutrient starvation.  Autophagy represents a fine regulated   specific susceptibility to dietary nonalcoholic steatohepatitis in mice. Lab
                           [12]
                                                                  Invest 2010;90:1437-46.
            mechanism to overcome cellular stress and promote cell   9.   Alisi A, Da Sacco L, Bruscalupi G, Piemonte F, Panera N, De Vito R,
            death  in  case  of  protracted  cellular  stress.  It  has  been   Leoni S, Bottazzo GF, Masotti A, Nobili V. Mirnome analysis reveals
            shown  that  its  modulation  can  be  a promising  target  for   novel molecular determinants in the pathogenesis of diet-induced
                                                                  nonalcoholic fatty liver disease. Lab Invest 2011;91:283-93.
            cancer therapy in liver cancer.  The expression of miRNAs   10.  Choi SE, Fu T, Seok S, Kim DH, Yu E, Lee KW, Kang Y, Li X, Kemper
                                    [13]
            repressing autophagy regulators like AMPK could highlight   B, Kemper JK. Elevated microRNA-34a in obesity reduces NAD+
            the variations occurring at epigenetic level conferring to cells   levels and SIRT1 activity  by directly  targeting  NAMPT.  Aging  Cell
            an altered metabolism that irreversibly modifies the liver cells   2013;12:1062-72.
            and tissue. These alterations could be responsible to trigger   11.  Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M,
            further pathological cellular features leading to cirrhosis and   Kato J, Tokunaga S, Sugihara TA, Hara Y, Hino K, Murawaki Y. A series
                                                                  of microrna in the chromosome 14q32.2 maternally imprinted region
            furthermore liver carcinogenesis. [14,15]  For this reason it will be   related to progression of non-alcoholic fatty liver disease in a mouse
            interesting to further focus on the expression of the miRNAs   model. PLoS One 2016;11:e0154676.
            localized at mat 14q32.2 in patients affected by cirrhosis and   12.  Ha J, Guan KL, Kim J. AMPK and autophagy in glucose/glycogen
            liver cancer, as it has been already shown for other miRNAs   metabolism. Mol Aspects Med 2015;46:46-62.
            in  liver  cancer  cells  and  thyroid  cancer. [16-18]   The  miRNAs   13.  Di Fazio P, Waldegger P, Jabari S, Lingelbach S, Montalbano R, Ocker M,
                                                                  Slater EP, Bartsch DK, Illig R, Neureiter D, Wissniowski TT. Autophagy-
            discovered in this study can represent valid targets for the   related cell death by pan-histone deacetylase inhibition in liver cancer.
            diagnosis of NAFLD and could be furthermore adopted as   Oncotarget 2016; doi: 10.18632/oncotarget.8585.
            biomarkers for patients affected by cirrhosis and liver cancer.  14.  Mahgoub  A, Steer CJ. MicroRNAs in the evaluation and potential
                                                                  treatment of liver diseases. J Clin Med 2016;5:52.
            Finally, inhibition of mTORC by the use of biguanides   15.  Kanda M, Sugimoto H, Kodera  Y. Genetic and epigenetic aspects
                                                                  of initiation and progression of hepatocellular carcinoma.  World J
                      [19]
            (metformin),  a well known mTOR inhibitors currently   Gastroenterol 2015;21:10584-97.
            used for the treatment of type 2 diabetes,  could represent   16.  Damanakis AI, Eckhardt S, Wunderlich A, Roth S, Wissniowski TT,
                                             [20]
            a therapeutic target for NASH  in a translational setting   Bartsch DK, Di Fazio P. MicroRNAs let7 expression in thyroid cancer:
                                     [21]
            defining mTORC as a major target of NASH related miRNA.  correlation with their deputed targets HMGA2 and SLC5A5. J Cancer
                                                                  Res Clin Oncol 2016;142:1213-20.
                                                              17.  Henrici A, Montalbano R, Neureiter D, Krause M, Stiewe T, Slater EP,
            Financial support and sponsorship                     Quint K, Ocker M, Di Fazio P. The pan-deacetylase inhibitor panobinostat
            Nil.                                                  suppresses the expression of oncogenic miRNAs in hepatocellular
                                                                  carcinoma cell lines. Mol Carcinog 2015;54:585-97.
            Conflicts of interest                             18.  Di Fazio P, Montalbano R, Neureiter D, Alinger B, Schmidt A, Merkel
            There are no conflicts of interest.                   AL, Quint K, Ocker M. Downregulation of HMGA2 by the pan-
                                                                  deacetylase inhibitor panobinostat is dependent on hsa-let-7b expression
                                                                  in liver cancer cell lines. Exp Cell Res 2012;318:1832-43.
            REFERENCES                                        19.  Khawaja MR, Nick AM, Madhusudanannair V, Fu S, Hong D, McQuinn
                                                                  LM, Ng CS, Piha-Paul SA, Janku F, Subbiah V, Tsimberidou A, Karp D,
            1.   Basaranoglu M, Basaranoglu G, Sabuncu T, Senturk H. Fructose as a key   Meric-Bernstam F, Lu KH, Naing A. Phase I dose escalation study of
                player in the development of fatty liver disease. World J Gastroenterol   temsirolimus in combination with metformin in patients with advanced/
                2013;19:1166-72.                                  refractory cancers. Cancer Chemother Pharmacol 2016;77:973-7.
            2.   Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology   20.  Provinciali N, Lazzeroni M, Cazzaniga M, Gorlero F, Dunn BK, DeCensi
                1998;114:842-5.                                   A. Metformin: risk-benefit profile with a focus on cancer. Expert Opin
            3.   Tilg  H,  Moschen  AR.  Evolution  of  inflammation  in  nonalcoholic   Drug Saf 2015;14:1573-85.
                fatty liver disease: the multiple parallel hits hypothesis.  Hepatology   21.  Xu H, Zhou Y, Liu YX, Ping J, Shou QY, Chen FM, Ruo R. Metformin
                2010;52:1836-46.                                  improves hepatic IRS2/PI3K/Akt signaling in insulin resistant rats of
            4.   Sanyal AJ, Brunt EM, Kleiner DE, Kowdley KV, Chalasani N, Lavine   NASH and cirrhosis. J Endocrinol 2016;229:133-44.







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