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• W4386133606 abstract "Liver cancer is one of the sixth most common cancers, a global threat to world cancer health, with 8,41,000 new cases and 782,000 deaths yearly worldwide per GLOBOCAN, 2018.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA A Cancer J. Clin. 2018; 68: 394-424Google Scholar Liver cancer mainly occurs in males, and 55% of the cases are of Chinese origin. Hepatocellular carcinoma (HCC) is one of the most common types of aggressive liver cancer, accounting for 90% of cases.1Bray F. Ferlay J. Soerjomataram I. Siegel R.L. Torre L.A. Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA A Cancer J. Clin. 2018; 68: 394-424Google Scholar,2Llovet J.M. Kelley R.K. Villanueva A. Singal A.G. Pikarsky E. Roayaie S. Lencioni R. Koike K. Zucman-Rossi J. Finn R.S. Hepatocellular carcinoma.Nat. Rev. Dis. Prim. 2021; 7: 6Google Scholar The endoplasmic reticulum (ER) plays a crucial role in protein processing, folding, transport, and quality control. Given the huge requirement of protein synthesis and folding in hepatocytes, hepatocytes are enriched with ER and are subjected to ER perturbation and stress.3Liu X. Green R.M. Endoplasmic reticulum stress and liver diseases.Liver Res. 2019; 3: 55-64Google Scholar ATF6 (activating transcription factor 6) is a key regulator of ER stress; however, the downstream targets and its role in HCC progression are not very clearly understood. In this issue, Yang and colleagues (https://doi.org/10.1016/j.omtn.2023.06.013) showed that ATF6 missense polymorphism is associated with HCC susceptibility.4Wu X. Li Y. Peng K. Zhou H. A missense polymorphism in ATF6 gene is associated with susceptibility to hepatocellular carcinoma probably by altering ATF6 level.Int. J. Cancer. 2014; 19: 61-66Google Scholar Given the function of ATF6 in regulating ER stress, the authors wanted to determine the molecular mechanism of ATF6 in HCC progression.5Yang X. Guo J. Li W. Li C. Zhu X. Liu Y. Wu X. PPM1H is down-regulated by ATF6 and dephosphorylates p-RPS6KB1 to inhibit progression of hepatocellular carcinoma.Mol. Ther. Nucleic Acids. 2023; 33: 164-179Google Scholar HCC is very aggressive, resulting in an overall shorter survival, where the 5-year survival is less than 10%. The prognosis of HCC depends on its stage, with early-stage HCC amenable to treatments with surgical resection, liver transplant, and local ablation.2Llovet J.M. Kelley R.K. Villanueva A. Singal A.G. Pikarsky E. Roayaie S. Lencioni R. Koike K. Zucman-Rossi J. Finn R.S. Hepatocellular carcinoma.Nat. Rev. Dis. Prim. 2021; 7: 6Google Scholar Conversely, advanced stages necessitate treatments such as multikinase inhibitors including sorafenib, lenvatinib, and others.6Llovet J.M. Pinyol R. Kelley R.K. El-Khoueiry A. Reeves H.L. Wang X.W. Gores G.J. Villanueva A. Molecular pathogenesis and systemic therapies for hepatocellular carcinoma.Nat Cancer. 2022; 3: 386-401Google Scholar A more recent approach involves the combination of PD-L1 immune checkpoint inhibitors and VEGF antagonists displaying more promising results than sorafenib, along with fewer side effects.7Tunissiolli N.M. Castanhole-Nunes M.M.U. Biselli-Chicote P.M. Pavarino É.C. da Silva R.F. da Silva R.d.C.M.A. Goloni-Bertollo E.M. Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy.Asian Pac. J. Cancer Prev. 2017; 18: 863-872Google Scholar Thus, there is an unmet need for more effective therapies and improved biomarkers for early detection of HCC. HCC develops from the interaction of tumors with microenvironment with genetic and environmental factors. Notable risk factors are hepatitis B or C viruses, chronic alcohol consumption, non-alcoholic fatty liver disease, and other genetic and non-genetic risk factors including primary biliary cirrhosis and autoimmune hepatitis, all leading to ER stress and dysfunction.7Tunissiolli N.M. Castanhole-Nunes M.M.U. Biselli-Chicote P.M. Pavarino É.C. da Silva R.F. da Silva R.d.C.M.A. Goloni-Bertollo E.M. Hepatocellular Carcinoma: a Comprehensive Review of Biomarkers, Clinical Aspects, and Therapy.Asian Pac. J. Cancer Prev. 2017; 18: 863-872Google Scholar Under stressful conditions such as heightened protein production, insufficient nutrients, or oxidative stress, the ER’s ability to properly fold proteins can falter, accumulating unfolded or misfolded protein, termed ER stress/unfolded protein response (UPR),8Zhang J. Guo J. Yang N. Huang Y. Hu T. Rao C. Endoplasmic reticulum stress-mediated cell death in liver injury.Cell Death Dis. 2022; 13: 1051Google Scholar which is intricately linked to the development of HCC. The UPR is activated by a cascade of events mainly mediated by three ER sensors: inositol requiring enzyme 1α (IRE1), protein kinase RNA-activated-like ER kinase (PERK), and activating transcription factor 6 (ATF6). Under normal conditions, the glucose-regulated protein 78 (GRP78), known as binding immunoglobulin protein, maintains each stress sensor in an inactive conformation by binding to their luminal domains. Nonetheless, during instances of ER stress, the GRP78 dissociates from each of these sensors, paving the way for activation. This, in turn, alleviates ER stress by mitigating the protein translation and eliminating misfolded proteins via ER-associated degradation and autophagy.8Zhang J. Guo J. Yang N. Huang Y. Hu T. Rao C. Endoplasmic reticulum stress-mediated cell death in liver injury.Cell Death Dis. 2022; 13: 1051Google Scholar,9Li X. Zhang K. Li Z. Unfolded protein response in cancer: the physician's perspective.J. Hematol. Oncol. 2011; 4: 8Google Scholar Upon UPR, ATF6, a type II ER transmembrane protein, is transferred to the Golgi apparatus and is cleaved to form the activated ATF6, regulating the transcription and expression of genes such as XBP1 that are essential for adapting to ER stress.10Madden E. Logue S.E. Healy S.J. Manie S. Samali A. The role of the unfolded protein response in cancer progression: From oncogenesis to chemoresistance.Biol. Cell. 2019; 111: 1-17Google Scholar Despite the upregulation of ATF6 and tumor-promoting role in the HCC, no reported studies have targeted ATF6; hence identifying the downstream targets of ATF6 is vital for understanding its role in HCC progression. Previously, the authors had found ATF6 polymorphism was associated with HCC progression. Furthermore, they established a conditional transgenic Atf6fl/fl mouse model with Alb-cre, which allows liver-specific deletion of Atf6. Firstly, the authors performed RNA-seq on ATF6-overexpressing (OE) HepG2 cells and Atf6fl/fl, and the cross-over analysis between the mouse and HepG2-ATF6 OE cells identified Ppm1h as one of the key dysregulated genes. Subsequently, through a series of experiments with overexpression and knockdown of ATF6 in HepG2 and Huh-7 cells, the authors elucidated the role of ATF6 in negatively regulating PPM1H expression using qPCR and immunoblot-based assays.5Yang X. Guo J. Li W. Li C. Zhu X. Liu Y. Wu X. PPM1H is down-regulated by ATF6 and dephosphorylates p-RPS6KB1 to inhibit progression of hepatocellular carcinoma.Mol. Ther. Nucleic Acids. 2023; 33: 164-179Google Scholar Further, using colony formation and invasion-migration assays, PPM1H overexpression inhibited the migration and invasion ability of HCC cell lines. This effect was accompanied by reduction in N-cadherin and vimentin protein expression, independent of ATF6 overexpression or knockdown, indicating it as a tumor suppressor downstream of ATF6 affecting epithelial to mesenchymal transition. PPM1H is a specific phosphatase of SMAD1/5/8 complex. The authors first validate the dephosphorylation of SMAD1 under the influence of PPM1H in Hep-G2 cells using immunoblot assays. Remarkably, even in the presence of LDN193189, which obstructs SMAD1 phosphorylation, cells overexpressing PPM1H continued to hinder migration and invasion. This intriguing outcome indicated the potential existence of additional substrates for PPM1H. To explore substrates of PPM1H, the authors performed computational molecular docking simulation and screened substrates containing serine/threonine within their active centers. Among the 16 substrates identified, the authors found the docking energy of RPS6KB1 to PPM1H lower than that of SMAD1, indicating it is a promising substrate. RPS6KB1, also known as S6K1, is a serine/threonine kinase activated by PI3K/mTOR signaling pathway. It governs critical cellular processes such as proliferation, glucose metabolism, autophagy, and survival. Notably, elevated levels of RPS6KB1 in HCC tissues have been associated with poor prognosis. Through coimmunoprecipitation-based experiments, the authors established the direct interaction of RPS6KB1 with PPM1H, which was enhanced by insulin. Moreover, they observed elevated RPS6KB1 phosphorylation levels on ATF6 overexpression, while ATF6 knockdown yielded the opposite effect, indicating ATF6’s role in promoting RPS6KB1 phosphorylation through PPM1H inhibition (Figure 1). Expanding on this, the overexpression of catalytically inactive mutants of RPS6KB1 (T389/412A and T389/412D, constitutive inactive mutant) led to significant difference in the phosphorylation of p-RPS6KB1 in cell lines with enhanced migration and invasion with PPM1H overexpression, indicating PPM1H-resulted phosphorylation of RPS6KB1 is associated with HCC progression. To determine the function of PPM1H in vivo, the authors used xenograft models such as Hep3B2.1-7 cell line stably overexpressing/knocking down PPM1H or ATF6. The authors found PPM1H knockdown enhanced the tumor growth, while PPM1H overexpression reduced the tumor growth, which could be partially neutralized by ATF6 overexpression, indicating PPM1H reduces tumorigenicity of HCC in vivo. Further, the authors use DEN/CCL4 injection in wild-type or Atf6Δhep mice to induce HCC and adenoviral overexpression of PPM1H. The authors found overexpressed PPM1H reduced the phosphorylation of RPS6KB1 by western blot with fewer tumor nodules in the ppm1h mice and reduced liver weight to body weight compared to respective controls, indicating the inhibitory role of PPM1H in HCC tumorigenesis. Finally, using immunohistochemical analysis of PPM1H in 134 HCC tissues, the authors showed lower expression of PPM1H correlated with shorter overall survival, indicating PPM1H may be a potential predictor of HCC patient prognosis. Overall, the authors used a combination of experimental and computational approaches to decipher the downstream targets of ATF6 and identify PPM1H as its downstream target in the context of HCC. ATF6’s impact on ER stress and its downstream effects were examined in Hep-G2 cells and an orthotopic mouse model of liver cancer. Furthermore, PPM1H emerged as a critical regulator of HCC behavior, influencing cell proliferation, migration, invasion, and EMT. PPM1H’s interaction with RPS6KB1 and its role in phosphorylation modulation was established. These findings shed light on the molecular mechanisms underlying ATF6-PPM1H interactions and their implications for hepatocellular carcinoma progression, providing valuable insights for potential therapeutic strategies targeting these pathways. Future studies with chemo and targeted therapy resistant liver cancer models could be used for studying the ATF6/PPM1H/RPS6K1 axis. The authors declare no competing interests." @default.
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• W4386133606 title "Unveiling ATF6 and PPM1H signaling in hepatocellular carcinoma progression: From ER stress to tumor suppression" @default.
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• W4386133606 doi "https://doi.org/10.1016/j.omtn.2023.08.008" @default.
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