benzyloxycarbonylleucyl-leucyl-leucine-aldehyde and Carcinogenesis

How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier.. TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of β-catenin, independent of HCC-associated β-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/β-catenin through APC stabilization and β-catenin cytosolic retention.. Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.

Topics: Adenomatous Polyposis Coli Protein; Animals; beta Catenin; Carbon Tetrachloride; Carcinogenesis; Carcinoma, Hepatocellular; Cell Nucleus; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Gene Knockout Techniques; HEK293 Cells; Hep G2 Cells; Humans; Leupeptins; Liver Neoplasms; Liver Regeneration; Lysosomes; Male; Membrane Proteins; Mice; Mice, Knockout; Proteolysis; Vacuolar Proton-Translocating ATPases; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

EBV-associated gastric carcinoma (EBVaGC) is a specific subgroup of gastric carcinoma, and the multifunctional transcriptional factor NF-κB may contribute to its tumorigenesis. In this study, we comprehensively characterized NF-κB signaling in EBVaGC using qRT-PCR, western blot, immunofluorescence assays, ELISA, and immunohistochemistry staining. NF-κB-signaling inhibitors may inhibit the growth of EBVaGC cells and induce significant apoptosis. IκBα is a key regulatory molecule, and repression of IκBα can contribute to aberrant NF-κB activation. Overexpression of LMP1 and LMP2A in the EBV-negative GC cell line SGC7901 could inhibit the expression of IκBα and induce NF-κB activation. These findings indicate that the canonical NF-κB signal is constitutively activated and plays an important role in EBVaGC tumorigenesis.

Topics: Carcinogenesis; Carcinoma; Cell Line, Tumor; Cell Proliferation; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Gene Expression Regulation, Neoplastic; Herpesvirus 4, Human; Humans; Leupeptins; NF-kappa B; NF-KappaB Inhibitor alpha; Nitriles; RNA, Small Interfering; Signal Transduction; Stomach Neoplasms; Sulfones; TNF Receptor-Associated Factor 1; Viral Matrix Proteins

Monocyte Chemoattractant protein-induced protein 1 (MCPIP1), also known as Regnase-1, is encoded by the ZC3H12a gene, and it mediates inflammatory processes by regulating the stability of transcripts coding for proinflammatory cytokines and controlling activity of transcription factors, such as NF-κB and AP1. We found that MCPIP1 transcript and protein levels are strongly downregulated in clear cell renal cell carcinoma (ccRCC) samples, which were derived from patients surgically treated for renal cancer compared to surrounded normal tissues. Using Caki-1 cells as a model, we analyzed the role of MCPIP1 in cancer development. We showed that MCPIP1 expression depends on the proteasome activity; however, hypoxia and hypoxia inducible factor 2 alfa (HIF2α) are key factors lowering MCPIP1 expression. Furthermore, we found that MCPIP1 negatively regulates HIF1α and HIF2α levels and in the case of the last one, the mechanism is based on the regulation of the half time of transcript coding for HIF2α. Enhanced expression of MCPIP1 in Caki-1 cells results in a downregulation of transcripts encoding VEGFA, GLUT1, and IL-6. Furthermore, MCPIP1 decreases the activity of mTOR and protein kinase B (Akt) in normoxic conditions. Taken together, MCPIP1 contributes to the ccRCC development.

Topics: Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors; Carcinogenesis; Carcinoma, Renal Cell; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Female; Glucose Transporter Type 1; Humans; Kidney Neoplasms; Leupeptins; Male; Middle Aged; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Proteasome Inhibitors; Ribonucleases; RNA, Messenger; Signal Transduction; Transcription Factors; Vascular Endothelial Growth Factor A

Malignant rhabdoid tumors (MRT), a pediatric cancer that most frequently appears in the kidney and brain, generally lack SNF5 (SMARCB1/INI1), a subunit of the SWI/SNF chromatin-remodeling complex. Recent studies have established that multiple SWI/SNF complexes exist due to the presence or absence of different complex members. Therefore, the effect of SNF5 loss upon SWI/SNF complex formation was investigated in human MRT cells. MRT cells and primary human tumors exhibited reduced levels of many complex proteins. Furthermore, reexpression of SNF5 increased SWI/SNF complex protein levels without concomitant increases in mRNA. Proteomic analysis, using mass spectrometry, of MRT cells before and after SNF5 reexpression indicated the recruitment of different components into the complex along with the expulsion of others. IP-Western blotting confirmed these results and demonstrated similar changes in other MRT cell lines. Finally, reduced expression of SNF5 in normal human fibroblasts led to altered levels of these same complex members. These data establish that SNF5 loss during MRT development alters the repertoire of available SWI/SNF complexes, generally disrupting those associated with cellular differentiation. These findings support a model where SNF5 inactivation blocks the conversion of growth-promoting SWI/SNF complexes to differentiation-inducing ones. Therefore, restoration of these complexes in tumors cells provides an attractive approach for the treatment of MRTs.. SNF5 loss dramatically alters SWI/SNF complex composition and prevents formation of complexes required for cellular differentiation.

Topics: Carcinogenesis; Cell Line, Tumor; Chromatin Assembly and Disassembly; Chromosomal Proteins, Non-Histone; DNA-Binding Proteins; Fibroblasts; Gene Expression Regulation, Neoplastic; Humans; Leupeptins; Proteasome Inhibitors; Rhabdoid Tumor; RNA, Messenger; SMARCB1 Protein; Transcription Factors; Transcription, Genetic