Project description:Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. We find that the creatine transporter solute carrier family 6, member 8 (SLC6A8) is upregulated in hypoxic HCC cells. Hypoxia-induced creatine accumulation drives metabolic reprogramming and antagonizes parthanatos. Pharmacological inhibition of SLC6A8 represents a promising therapeutic strategy for HCC.
Project description:Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models.
Project description:Hepatocellular carcinoma (HCC) is a formidable malignancy with limited effective therapeutic avenues. This study was designed to investigate the role of transglutaminase 2 (TGM2) in promoting HCC progression and assess its potential as a target for therapeutic intervention in HCC treatment.TMG2 expression was positively related to a higher AFP level, poor differentiation, and a later BCLC stage. Tgm2 deficiency or H3Q5ser inhibition notably restrained HCC progression. Mechanism research revealed that TGM2-mediated H3Q5ser modifications promote HCC progression via MYC pathway signaling. Furthermore, transcriptional intermediary factor 1 beta (TIF1-β/TRIM28) mediated the recruitment of TGM2 by MYC to facilitate H3Q5ser modifications on MYC targets. Finally, targeting the TGM2 transglutaminase activity significantly suppressed HCC progression in preclinical models.
Project description:Recently, a PARP1-dependent cell-death process termed "parthanatos", driven by DNA damage, has emerged as a crucial regulator of tissue homeostasis and tumorigenesis. Hypoxia is a hallmark of solid tumors and profoundly affects the malignant phenotypes of cancer cells. The crosstalk between parthanatos and hypoxia remains poorly understood. In our study, we find that despite causing DNA damage, hypoxia fails to induce parthanatos in HCC. Transcriptome sequencing upon MNNG stimulation indicated that the creatine transporter solute carrier family 6, member 8 (SLC6A8) was involved in parthanatos antagonism and malignant phenotypes in hypoxic HCC cells.
Project description:Hypoxic microenvironment plays a critical role in solid tumor progression. More and more protein coding and non-coding RNA genes have been identified as hypoxia-regulated genes in HCC. Thus, we attempted to identify more novel hypoxia-regulated genes in HCC with Hep3B cells exposed to 20% or 1% oxygen.
Project description:The prognosis of hepatocellular carcinoma (HCC) is poor due to the high incidence of intrahepatic metastasis. The aim of this study is to investigate the mechanism of intrahepatic metastasis in HCC via extracellular vesicles (EVs).
Project description:Endocytosis is a cellular function which is likely to take part in HCC development due to its important role in regulating the abundances of vital signaling receptors. In this study, we aimed to investigate the expression of endocytosis-associated proteins in HCCs with various differentiation grades. Therefore, we analyzed 36 tissue specimens from HCC patients via label-free LC-MS/MS including 19 HCC tissue samples with different degrees of histological grades and 17 corresponding non-tumorous tissue controls. Following label-free analysis the abundances of SCAMP3 and CLTC were immunohistochemically examined in tissue sections of 84 HCC patients. We demonstrate the novel association of several endocytosis-associated proteins, in particular SCAMP3 with HCC progression.
Project description:Limb expression 1-like protein (LIX1L) plays important role in various liver disorders, but its role and underlying mechanism in nonalcoholic hepatitis (NASH) and HCC progression remains obscure. Here, we report that LIX1L functions as a key integrative regulator linking lipid metabolism and inflammation, adipose tissue dysfunction and hepatic microenvironment reprogramming which promotes NASH progression. LIX1L significantly upregulated in NAFLD/NASH patients, mouse models and palmitic acid-stimulated hepatocytes. Lix1l deletion inhibits lipid deposition, inflammatory response and fibrosis in liver as well as adipocyte differentiation by downregulation of fatty acid translocase CD36 expression, alleviating NASH and associated HCC progression. In contrast, adeno-associated virus (AAV)-mediated LIX1L overexpression exacerbates NASH progression in mice. Mechanistically, metabolic stress promotes PARP1 mediated poly-ADP-ribosylation (PARylation) of LIX1L, subsequently increasing the stability and RNA binding ability of LIX1L protein. LIX1L binds to AU-rich element (ARE) in the 3’ untranslated region (UTR) of CD36 mRNA, thus attenuating CD36 mRNA decay. In NASH and associated HCC mouse models, LIX1L deficiency-mediated downregulation of CD36 suppresses adipogenesis, hepatic lipid uptake, and reprograms the tumor-prone liver microenvironment with increased cytotoxic T lymphocytes (CTLs), reduced immunosuppressive cell proportions. These data indicate a systematic function of LIX1L in the pathogenesis of NASH and underscore the PARP1/LIX1L/CD36 axis as a potential target for treatment of NASH and associated HCC.
Project description:HCC has a poor response to therapy and a bad prognosis with chronic inflammation be the most common etiologies for HCC progression. Here we report a redox-dependent regulation mechanism of PIR protein nuclear shuttling, leading to liver inflammation and HCC progression.