Back to Search
Start Over
PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism.
- Source :
-
Cancer research [Cancer Res] 2018 Aug 15; Vol. 78 (16), pp. 4471-4481. Date of Electronic Publication: 2018 Jul 02. - Publication Year :
- 2018
-
Abstract
- Glucose metabolic reprogramming from oxidative phosphorylation to glycolysis is one of the hallmarks of cancer development. Coenzyme Q10 (CoQ10) is essential for electron transport in the mitochondrial respiratory chain and for antioxidant defense. Here, we investigated the role of a key factor in CoQ10 synthesis, prenyldiphosphate synthase subunit 2 ( PDSS2 ), in hepatocellular carcinoma (HCC) tumorigenesis. PDSS2 was frequently downregulated in HCC tissues and was significantly associated with poorer HCC prognosis ( P = 0.027). PDSS2 downregulation was a prognostic factor independent of T status and stage ( P = 0.028). Downregulation of CoQ10 was significantly correlated with downregulation of PDSS2 in HCC tumor tissues ( R = 0.414; P < 0.001). Of the six different splicing isoforms of PDSS2, the five variants other than full-length PDSS2 showed loss of function in HCC. Reintroduction of full-length PDSS2 into HCC cells increased CoQ10 and mitochondrial electron transport complex I activity and subsequently induced a metabolic shift from aerobic glycolysis to mitochondrial respiration in cells. Reintroduction of PDSS2 also inhibited foci formation, colony formation in soft agar, and tumor formation in nude mice. Knockdown of PDSS2 induced chromosomal instability in the MIHA immortalized human liver cell line. Furthermore, knockdown of PDSS2 in MIHA induced malignant transformation. Overall, our findings indicate that PDSS2 deficiency might be a novel driving factor in HCC development. Significance: Downregulation of PDSS2 is a driving factor in hepatocellular carcinoma tumorigenesis. Cancer Res; 78(16); 4471-81. ©2018 AACR .<br /> (©2018 American Association for Cancer Research.)
- Subjects :
- Animals
Biomarkers, Tumor genetics
Carcinogenesis genetics
Carcinoma, Hepatocellular metabolism
Carcinoma, Hepatocellular pathology
Cellular Reprogramming genetics
Gene Expression Regulation, Neoplastic
Glucose metabolism
Glycolysis genetics
Humans
Liver metabolism
Liver pathology
Liver Neoplasms metabolism
Liver Neoplasms pathology
Mice
Mitochondria metabolism
Mitochondria pathology
Nitric Oxide Synthase genetics
Xenograft Model Antitumor Assays
Alkyl and Aryl Transferases genetics
Carcinoma, Hepatocellular genetics
Liver Neoplasms genetics
Mitochondria genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 78
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 29967258
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-17-2172