PDSS2 Deficiency Induces Hepatocarcinogenesis by Decreasing Mitochondrial Respiration and Reprogramming Glucose Metabolism
| Autor: | Wen Deng, Yumin Hu, Yunfei Yuan, Xiaojiao Ban, Shuhai Lin, Zongwei Cai, Lei Li, Yan Li, Jinjun Li, Ying Hui Zhu, Tingting Zeng, Ying Zhou, Song Gao, Dan Xie, Zhi Tang, Peng Huang, Xiao-Shi Zhang, Xin Yuan Guan |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Chemistry Oxidative phosphorylation medicine.disease_cause Malignant transformation 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Mitochondrial respiratory chain Oncology Downregulation and upregulation PDSS2 Anaerobic glycolysis 030220 oncology & carcinogenesis medicine Cancer research Glycolysis Carcinogenesis |
| Zdroj: | Cancer Research. 78:4471-4481 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-2172 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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