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RESEARCH PRODUCT
Copper/MYC/CTR1 interplay: A dangerous relationship in hepatocellular carcinoma
Maurizio MartiniLaura AntonucciBarbara BarbaroLuca MieleClara BalsanoBarbara IlliSergio NasiCristiana PorcuAnna LicataAntonio Griecosubject
0301 basic medicineCirrhosisCopper; CTR1; Hepatocellular carcinoma; MYC; Non alcoholic fatty liver disease; OncologyMYCMetastasis03 medical and health sciencesmedicineOncogeneCell growthChemistryFatty liverCTR1hepatocellular carcinomaHCCSmedicine.diseasedigestive system diseases3. Good health030104 developmental biologyOncologyHepatocellular carcinomacopperCancer researchCTR1; MYC; copper; hepatocellular carcinoma; non alcoholic fatty liver diseaseLiver cancerResearch Papernon alcoholic fatty liver diseasedescription
Free serum copper correlates with tumor incidence and progression of human cancers, including hepatocellular carcinoma (HCC). Copper extracellular uptake is provided by the transporter CTR1, whose expression is regulated to avoid excessive intracellular copper entry. Inadequate copper serum concentration is involved in the pathogenesis of Non Alcoholic Fatty Liver Disease (NAFLD), which is becoming a major cause of liver damage progression and HCC incidence. Finally, MYC is over-expressed in most of HCCs and is a critical regulator of cellular growth, tumor invasion and metastasis. The purpose of our study was to understand if higher serum copper concentrations might be involved in the progression of NAFLD-cirrhosis toward-HCC. We investigated whether high exogenous copper levels sensitize liver cells to transformation and if it exists an interplay between copper-related proteins and MYC oncogene. NAFLD-cirrhotic patients were characterized by a statistical significant enhancement of serum copper levels, even more evident in HCC patients. We demonstrated that high extracellular copper concentrations increase cell growth, migration, and invasion of liver cancer cells by modulating MYC/CTR1 axis. We highlighted that MYC binds a specific region of the CTR1 promoter, regulating its transcription. Accordingly, CTR1 and MYC proteins expression were progressively up-regulated in liver tissues from NAFLD-cirrhotic to HCC patients. This work provides novel insights on the molecular mechanisms by which copper may favor the progression from cirrhosis to cancer. The Cu/MYC/CTR1 interplay opens a window to refine HCC diagnosis and design new combined therapies.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-01 |