Potentials of ribosomopathy gene as pharmaceutical targets for cancer treatment

Ribosomopathies encompass a spectrum of disorders arising from impaired ribosome biogenesis and reduced functionality.Mutation or dysexpression of the genes that disturb any finely regulated steps of ribosome biogenesis can result in different types of ribosomopathies in clinic,collectively known as ribosomopathy genes.Emerging data suggest that ribosomopathy patients exhibit a significantly heightened susceptibility to cancer.Abnormal ribosome biogenesis and dysregulation of some ribosomopathy genes have also been found to be intimately associated with cancer development.The correlation between ribosome biogenesis or ribosomopathy and the development of malignancies has been well established.This work aims to review the recent advances in the research of ribosomopathy genes among human cancers and meanwhile,to excavate the potential role of these genes,which have not or rarely been reported in cancer,in the disease development across cancers.We plan to establish a theoretical framework between the ribosomopathy gene and cancer development,to further facilitate the potential of these genes as diagnostic biomarker as well as pharmaceutical targets for cancer treatment.

MicroRNA-216a: a potential therapeutic target for drug resistance and recurrent of liver cancer

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Decoding m^(6)A mRNA methylation by reader proteins in liver diseases

N6-methyladenosine(m^(6)A)is a dynamic and reversible epigenetic regulation.As the most prevalent internal post-transcriptional modification in eukaryotic RNA,it participates in the regulation of gene expression through various mechanisms,such as mRNA splicing,nuclear export,localization,translation efficiency,mRNA stability,and structural transformation.The involvement of m^(6)A in the regulation of gene expression depends on the specific recognition of m^(6)A-modified RNA by reader proteins.In the pathogenesis and treatment of liver disease,studies have found that the expression levels of key genes that promote or inhibit the development of liver disease are regulated by m^(6)A modification,in which abnormal expression of reader proteins determines the fate of these gene transcripts.In this review,we introduce m^(6)A readers,summarize the recognition and regulatory mechanisms of m^(6)A readers on mRNA,and focus on the biological functions and mechanisms of m^(6)A readers in liver cancer,viral hepatitis,non-alcoholic fatty liver disease(NAFLD),hepatic fibrosis(HF),acute liver injury(ALI),and other liver diseases.This information is expected to be of high value to researchers deciphering the links between m^(6)A readers and human liver diseases.

Melatonin, a novel selective ATF-6 inhibitor, induces human hepatoma cell apoptosis through COX-2 downregulation

AIM To clarify the mechanisms involved in the critical endoplasmic reticulum(ER) stress initiating unfolded protein response pathway modified by melatonin.METHODS Hepatoma cells, Hep G2, were cultured in vitro. Flow cytometry and TUNEL assay were used to measure Hep G2 cell apoptosis. Western blotting and quantitative reverse transcription-polymerase chain reaction methods were used to determine the protein and messenger RNA levels of ER stress and apoptosis related genes' expression, respectively. Tissue microarray construction from patients was verified by immunohistochemical analysis.RESULTS In the present study, we first identified that melatoninselectively blocked activating transcription factor 6(ATF-6) and then inhibited cyclooxygenase-2 (COX-2) expression, leading to enhanced liver cancer cell apoptosis under ER stress condition. Dramatically increased CCAAT-enhancer-binding protein homologous protein level, suppressed COX-2 and decreased Bcl-2/Bax ratio by melatonin or ATF-6 si RNA contributed the enhanced Hep G2 cell apoptosis under tunicamycin (an ER stress inducer) stimulation. In clinical hepatocellular carcinoma patients, the close relationship between ATF-6 and COX-2 was further confirmed.CONCLUSION These findings indicate that melatonin as a novel selective ATF-6 inhibitor can sensitize human hepatoma cells to ER stress inducing apoptosis.

MicroRNA let-7a： a novel therapeutic candidate in prostate cancer

Dear Editor, It is known that microRNA let-7a can be useful for diagnosis and therapy of cancer, including prostate cancer （PCa）.1 A recent article by Wang et al. 2 comprehensively showed that let-7al could inhibit the expression of insulin-like growth factor- 1 receptor （IGF 1 R） by directly targeting the T1 and T2 sites in the 3＇ untranslated region （3＇UTR） of IGF 1R mRNA. Furthermore, they found that let-7a 1-mediated IGF I R downregulation was accompanied by attenuation of Elk1 activity and c-fos expression, inhibition of PC-3 cell proliferation, cell cycle arrest and induced apoptosis and that inhibition oflet-7al could up-regulate IGF 1R accompanied by an increase of Elk1 activity and c-fos expression,

Application and progress of the detection technologies in hepatocellular carcinoma

Hepatocellular carcinoma(HCC)has a very high incidence and fatality rate,and in most cases,it is already at an advanced stage when diagnosed.Therefore,early prevention and detection of HCC are two of the most effective strategies.However,the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy,which is known as the“gold standard”.In this review,we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring,and found that in addition to the traditional imaging detection and liver biopsy,alpha fetoprotein(AFP),lens culinaris-agglutinin-reactive fraction of AFP(AFP-L3),protein induced by vitamin K absence or antagonist-II(PIVKA-II)and other biomarkers are excellent biomarkers for HCC,especially when they are combined together.Most notably,the emerging liquid biopsy shows great promise in detecting HCC.In addition,lactic dehydrogenase(LDH),suppressor of cytokine signaling(SOCS)and other relevant biomarkers may become promising biomarkers for HCC post-treatment monitoring.Through the detailed introduction of the diagnostic technology of HCC,we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis,to improve the diagnostic rate of HCC and reduce its mortality.

Puerarin inhibits inflammation and lipid accumulation in alcoholic liver disease through regulating MMP8

Alcoholic liver disease(ALD)is a growing global health concern,and its early pathogenesis includes steatosis and steatohepatitis.Inhibiting lipid accumulation and inflammation is a crucial step in relieving ALD.Evidence shows that puerarin(Pue),an isoflavone isolated from Pueraria lobata,exerts cardio-protective,neuroprotective,anti-inflammatory,antioxidant activities.However,the therapeutic potential of Pue on ALD remains unknown.In the study,both the NIAAA model and ethanol(EtOH)-induced AML-12 cell were used to explore the protective effect of Pue on alcoholic liver injury in vivo and in vitro and related mechanism.The results showed that Pue(100 mg·kg^(−1))attenuated EtOH-induced liver injury and inhibited the levels of SREBP-1c,TNF-α,IL-6 and IL-1β,compared with silymarin(Sil,100 mg·kg^(−1)).In vitro results were consistent with in vivo results.Mechanistically,Pue might suppress liver lipid accumulation and inflammation by regulating MMP8.In conclusion,Pue might be a promising clinical candidate for ALD treatment.

P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis

Alcoholic liver disease is one of the most common chronic liver diseases in the world.It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea,vomiting,enlargement of the liver,and jaundice.Recent studies suggest that Kupffer cell-mediated inflam-matory response is a core driver in the development of alco-holic steatohepatitis and alcoholic liver fibrosis.As a danger signal,extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor,the ac-tivated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs.Active caspase-1 promotes the conversion of pro-IL-1βto IL-1β,which fur-ther enhances the inflammatory response.Here,we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis.Reg-ulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.